Progress in biophysics and molecular biology, Jan 13, 2015
DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the imm... more DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. This review describes the current progress of the structural biology of DCC with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
Netrin-1 is a guidance cue that can trigger either attraction or repulsion effects on migrating a... more Netrin-1 is a guidance cue that can trigger either attraction or repulsion effects on migrating axons of neurons, depending on the repertoire of receptors available on the growth cone. How a single chemotropic molecule can act in such contradictory ways has long been a puzzle at the molecular level. Here we present the crystal structure of netrin-1 in complex with the Deleted in Colorectal Cancer (DCC) receptor. We show that one netrin-1 molecule can simultaneously bind to two DCC molecules through a DCC-specific site and through a unique generic receptor binding site, where sulfate ions staple together positively charged patches on both DCC and netrin-1. Furthermore, we demonstrate that UNC5A can replace DCC on the generic receptor binding site to switch the response from attraction to repulsion. We propose that the modularity of binding allows for the association of other netrin receptors at the generic binding site, eliciting alternative turning responses.
Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 and PHF5A The structure suggests a model in which splicing modulators interfere with branch poin...
Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of ... more Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of tissue repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold (Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats. LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion (15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic activity (50-1000μg/mL) was observed in marigold oil. In the wound healing rat model, the LGP (15mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7, but reduced leukocyte recruitment after 14 and 21days, as compared to the control. Additionally, collagen production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of re-epithelialization of the wound itself. The methodology utilized in the present study has produced a potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve the wound healing process.
Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 R1074H and PHF5A Y36C. The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure–activity relationship (SAR) on the PHF5A R38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.
Graphical Abstract Highlights d The first atomic structure of a human spliceosome d The conformat... more Graphical Abstract Highlights d The first atomic structure of a human spliceosome d The conformation of the spliceosome just prior to exon ligation d Mechanistic insights on Prp17, Slu7, PRKRIP1, and the EJC d Intron interlocked with RBM22 suggests mechanisms of intron recruitment and release In Brief The first atomic structure of human spliceosome reveals important insights into exon ligation.
Progress in Biophysics and Molecular Biology, Apr 15, 2015
DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the imm... more DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin
superfamily. It was originally identified as a prognostic tumor marker and then subsequently
found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other
important cellular processes. This review describes the current progress of the structural biology of DCC
with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as
well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands
and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
European Journal of Pharmaceutical Sciences, Feb 12, 2015
Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of ... more Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of tissue
repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold
(Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats.
LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP
emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation
was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In
addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion
(15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good
stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic
activity (50–1000 lg/mL) was observed in marigold oil. In the wound healing rat model, the LGP
(15 mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7,
but reduced leukocyte recruitment after 14 and 21 days, as compared to the control. Additionally, collagen
production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of
re-epithelialization of the wound itself. The methodology utilized in the present study has produced a
potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve
the wound healing process.
Drugs that can protect against organ damage are urgently needed, especially for diseases such as ... more Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed 1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline′s ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
Netrin-1 is a guidance cue that can trigger either
attraction or repulsion effects on migrating ... more Netrin-1 is a guidance cue that can trigger either
attraction or repulsion effects on migrating axons of
neurons, depending on the repertoire of receptors
available on the growth cone. How a single chemotropic
molecule can act in such contradictory ways
has long been a puzzle at the molecular level. Here
wepresent the crystal structure of netrin-1 in complex
with the Deleted in Colorectal Cancer (DCC) receptor.
We show that one netrin-1 molecule can simultaneously
bind to two DCC molecules through a DCCspecific
site and through a unique generic receptor
binding site, where sulfate ions staple together positively
charged patches on both DCC and netrin-1.
Furthermore, we demonstrate that UNC5A can
replace DCC on the generic receptor binding site to
switch the response from attraction to repulsion. We
propose that the modularity of binding allows for the
association of other netrin receptors at the generic
binding site, eliciting alternative turning responses.
Progress in biophysics and molecular biology, Jan 13, 2015
DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the imm... more DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. This review describes the current progress of the structural biology of DCC with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
Netrin-1 is a guidance cue that can trigger either attraction or repulsion effects on migrating a... more Netrin-1 is a guidance cue that can trigger either attraction or repulsion effects on migrating axons of neurons, depending on the repertoire of receptors available on the growth cone. How a single chemotropic molecule can act in such contradictory ways has long been a puzzle at the molecular level. Here we present the crystal structure of netrin-1 in complex with the Deleted in Colorectal Cancer (DCC) receptor. We show that one netrin-1 molecule can simultaneously bind to two DCC molecules through a DCC-specific site and through a unique generic receptor binding site, where sulfate ions staple together positively charged patches on both DCC and netrin-1. Furthermore, we demonstrate that UNC5A can replace DCC on the generic receptor binding site to switch the response from attraction to repulsion. We propose that the modularity of binding allows for the association of other netrin receptors at the generic binding site, eliciting alternative turning responses.
Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 and PHF5A The structure suggests a model in which splicing modulators interfere with branch poin...
Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of ... more Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of tissue repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold (Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats. LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion (15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic activity (50-1000μg/mL) was observed in marigold oil. In the wound healing rat model, the LGP (15mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7, but reduced leukocyte recruitment after 14 and 21days, as compared to the control. Additionally, collagen production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of re-epithelialization of the wound itself. The methodology utilized in the present study has produced a potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve the wound healing process.
Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 R1074H and PHF5A Y36C. The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure–activity relationship (SAR) on the PHF5A R38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.
Graphical Abstract Highlights d The first atomic structure of a human spliceosome d The conformat... more Graphical Abstract Highlights d The first atomic structure of a human spliceosome d The conformation of the spliceosome just prior to exon ligation d Mechanistic insights on Prp17, Slu7, PRKRIP1, and the EJC d Intron interlocked with RBM22 suggests mechanisms of intron recruitment and release In Brief The first atomic structure of human spliceosome reveals important insights into exon ligation.
Progress in Biophysics and Molecular Biology, Apr 15, 2015
DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the imm... more DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin
superfamily. It was originally identified as a prognostic tumor marker and then subsequently
found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other
important cellular processes. This review describes the current progress of the structural biology of DCC
with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as
well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands
and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
European Journal of Pharmaceutical Sciences, Feb 12, 2015
Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of ... more Appropriate therapeutics for wound treatments can be achieved by studying the pathophysiology of tissue
repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold
(Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats.
LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP
emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation
was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In
addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion
(15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good
stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic
activity (50–1000 lg/mL) was observed in marigold oil. In the wound healing rat model, the LGP
(15 mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7,
but reduced leukocyte recruitment after 14 and 21 days, as compared to the control. Additionally, collagen
production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of
re-epithelialization of the wound itself. The methodology utilized in the present study has produced a
potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve
the wound healing process.
Drugs that can protect against organ damage are urgently needed, especially for diseases such as ... more Drugs that can protect against organ damage are urgently needed, especially for diseases such as sepsis and brain stroke. We discovered that terazosin (TZ), a widely marketed 1-adrenergic receptor antagonist, alleviated organ damage and improved survival in rodent models of stroke and sepsis. Through combined studies of enzymology and X-ray crystallography, we discovered that TZ binds a new target, phosphoglycerate kinase 1 (Pgk1), and activates its enzymatic activity, probably through 2,4-diamino-6,7-dimethoxyisoquinoline′s ability to promote ATP release from Pgk1. Mechanistically, the ATP generated from Pgk1 may enhance the chaperone activity of Hsp90, an ATPase known to associate with Pgk1. Upon activation, Hsp90 promotes multistress resistance. Our studies demonstrate that TZ has a new protein target, Pgk1, and reveal its corresponding biological effect. As a clinical drug, TZ may be quickly translated into treatments for diseases including stroke and sepsis.
Netrin-1 is a guidance cue that can trigger either
attraction or repulsion effects on migrating ... more Netrin-1 is a guidance cue that can trigger either
attraction or repulsion effects on migrating axons of
neurons, depending on the repertoire of receptors
available on the growth cone. How a single chemotropic
molecule can act in such contradictory ways
has long been a puzzle at the molecular level. Here
wepresent the crystal structure of netrin-1 in complex
with the Deleted in Colorectal Cancer (DCC) receptor.
We show that one netrin-1 molecule can simultaneously
bind to two DCC molecules through a DCCspecific
site and through a unique generic receptor
binding site, where sulfate ions staple together positively
charged patches on both DCC and netrin-1.
Furthermore, we demonstrate that UNC5A can
replace DCC on the generic receptor binding site to
switch the response from attraction to repulsion. We
propose that the modularity of binding allows for the
association of other netrin receptors at the generic
binding site, eliciting alternative turning responses.
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Papers by Lorenzo Finci
superfamily. It was originally identified as a prognostic tumor marker and then subsequently
found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other
important cellular processes. This review describes the current progress of the structural biology of DCC
with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as
well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands
and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold
(Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats.
LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP
emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation
was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In
addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion
(15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good
stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic
activity (50–1000 lg/mL) was observed in marigold oil. In the wound healing rat model, the LGP
(15 mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7,
but reduced leukocyte recruitment after 14 and 21 days, as compared to the control. Additionally, collagen
production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of
re-epithelialization of the wound itself. The methodology utilized in the present study has produced a
potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve
the wound healing process.
attraction or repulsion effects on migrating axons of
neurons, depending on the repertoire of receptors
available on the growth cone. How a single chemotropic
molecule can act in such contradictory ways
has long been a puzzle at the molecular level. Here
wepresent the crystal structure of netrin-1 in complex
with the Deleted in Colorectal Cancer (DCC) receptor.
We show that one netrin-1 molecule can simultaneously
bind to two DCC molecules through a DCCspecific
site and through a unique generic receptor
binding site, where sulfate ions staple together positively
charged patches on both DCC and netrin-1.
Furthermore, we demonstrate that UNC5A can
replace DCC on the generic receptor binding site to
switch the response from attraction to repulsion. We
propose that the modularity of binding allows for the
association of other netrin receptors at the generic
binding site, eliciting alternative turning responses.
superfamily. It was originally identified as a prognostic tumor marker and then subsequently
found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other
important cellular processes. This review describes the current progress of the structural biology of DCC
with an emphasis on how DCC is involved in the dual functionality of netrin-1 as a chemo-attractant as
well as a repellent in axon guidance, referred to as bi-functionality. A perspective about other DCC ligands
and the signaling mechanism of the cytoplasmic tail of DCC is also recapitulated.
repair. Here we develop formulations of lamellar gel phase (LGP) emulsions containing marigold
(Calendula officinalis) oil, evaluating their stability and activity on experimental wound healing in rats.
LGP emulsions were developed and evaluated based on a phase ternary diagram to select the best LGP
emulsion, having a good amount of anisotropic structure and stability. The selected LGP formulation
was analyzed according to the intrinsic and accelerated physical stability at different temperatures. In
addition, in vitro and in vivo studies were carried out on wound healing rats as a model. The LGP emulsion
(15.0% marigold oil; 10.0% of blend surfactants and 75.0% of purified water [w/w/w]) demonstrated good
stability and high viscosity, suggesting longer contact of the formulation with the wound. No cytotoxic
activity (50–1000 lg/mL) was observed in marigold oil. In the wound healing rat model, the LGP
(15 mg/mL) showed an increase in the leukocyte recruitment to the wound at least on days 2 and 7,
but reduced leukocyte recruitment after 14 and 21 days, as compared to the control. Additionally, collagen
production was reduced in the LGP emulsion on days 2 and 7 and further accelerated the process of
re-epithelialization of the wound itself. The methodology utilized in the present study has produced a
potentially useful formulation for a stable LGP emulsion-containing marigold, which was able to improve
the wound healing process.
attraction or repulsion effects on migrating axons of
neurons, depending on the repertoire of receptors
available on the growth cone. How a single chemotropic
molecule can act in such contradictory ways
has long been a puzzle at the molecular level. Here
wepresent the crystal structure of netrin-1 in complex
with the Deleted in Colorectal Cancer (DCC) receptor.
We show that one netrin-1 molecule can simultaneously
bind to two DCC molecules through a DCCspecific
site and through a unique generic receptor
binding site, where sulfate ions staple together positively
charged patches on both DCC and netrin-1.
Furthermore, we demonstrate that UNC5A can
replace DCC on the generic receptor binding site to
switch the response from attraction to repulsion. We
propose that the modularity of binding allows for the
association of other netrin receptors at the generic
binding site, eliciting alternative turning responses.