The Experts below are selected from a list of 915 Experts worldwide ranked by ideXlab platform
Ming-hai Wang - One of the best experts on this subject based on the ideXlab platform.
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Preclinical Efficacy of Anti-RON Antibody-Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase.
Molecular Pharmaceutics, 2018Co-Authors: Hangping Yao, Liang Feng, Tian-hao Weng, Sreedhar Reddy Suthe, A.g.m. Mostofa, Linghui Chen, Weilin Wang, Ming-hai WangAbstract:Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody–drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema Domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly...
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Preclinical Efficacy of Anti-RON Antibody–Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase
2018Co-Authors: Hangping Yao, Liang Feng, Tian-hao Weng, Sreedhar Reddy Suthe, A.g.m. Mostofa, Linghui Chen, Weilin Wang, Ming-hai WangAbstract:Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody–drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema Domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies
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Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire Sema sequence
International Journal of Oncology, 2010Co-Authors: Kun Zhang, Hangping Yao, Yong-qing Zhou, Snehal S Padhye, Ming-hai WangAbstract:The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant is an 85 kDa soluble protein from an mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop codon leading to the formation of a RON variant consisting of the entire 35 kDa alpha-chain and a 45 kDa partial extracellular beta-chain. The protein was featured by a Sema Domain, a hinge motif and a portion of the first IPT unit (designated as RONDelta85). RONDelta85 binds directly to MSP, forms MSP-RONDelta85 complex, and inhibits RON phosphorylation. RONDelta85 disrupts RON or RONDelta160 dimerization, prevents their phosphorylation, and attenuates downstream signaling events. The action of RONDelta85 is specific to RON and has no effect on MET and EGFR. In colon and pancreatic cancer cells, RONDelta85 inhibits spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RONDelta85 also inhibits spontaneous and MSP-induced cell migration. We conclude that RONDelta85 is an antagonist to the MSP-RON pathway, which has potential for regulating RON/RON160-mediated tumorigenic activities.
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Abstract B240: Inhibition of MSP‐RON signaling pathway in cancer cells by a novel soluble form of RON variant containing the complete Sema sequences
Molecular Cancer Therapeutics, 2009Co-Authors: Kun Zhang, Ming-hai WangAbstract:The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON‐MSP pathway in various cancer cells. The variant was an 85 kDa soluble protein from a mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop code leading to a RON variant composed of a full 35kDa α‐chain and a 45 kDa partial extracellular β‐chain. The protein was featured by a Sema Domain, a hinge and a portion of the first IPT unit (designated as RON 85). RON 85 directly bound to the MSP, formed the MSP‐RON 85 complex, and inhibited RON phosphorylation. RON 85 disrupted RON or RON 160 dimerization, prevented their phosphorylation, and attenuated their downstream signaling events. The action of RON 85 was specific to RON and had no effect on MET and EGFR. In colon and pancreatic cancer cells, RON 85 inhibited spontaneous or MSP‐induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RON 85 also inhibited spontaneous or MSP‐induced cell migration. We concluded that RON 85 is an antagonist to the MSP‐RON pathway with therapeutic potentials for controlling tumorigenic phenotypes of cancer cells. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B240.
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Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets.
Cancer Letters, 2007Co-Authors: Hangping Yao, Ming-hai WangAbstract:Abstract Aberrant expression of the RON (Recepteur d’Origine Nantais) receptor tyrosine kinase, accompanied by generation of multiple splicing or truncated variants, contributes to pathogenesis of epithelial cancers. Currently, six variants including RONΔ170, Δ165, Δ160, Δ155, Δ110, and Δ55 with various deletions or truncations in the extracellular or intracellular regions have been identified. The extracellular sequences contain functional structures such as Sema Domain, PSI motif, and IPT units. The deletion or truncation results in constitutive phosphorylation and increased kinase activities. Oncogenic RONΔ160, generated by exclusion of the first IPT unit, is a typical example. In contrast, the deletion adjacent to the conserved MET 1254 in the kinase Domain converts RON into a dominant negative agent. Among three mechanisms underlying isoform production, the switch from constitutive to alternative pre-mRNA splicing is the major event in producing RON variants in cancer cells. Most of the RON variants have the ability to activate multiple signaling cascades with a different substrate specificity and phosphorylation profile. They regulate cell migration, invasion, and proliferation, which contribute to the invasive phenotype and promote the malignant progression. Thus, determining the pathogenesis of RON variants is critical in understanding the mechanisms underlying cancer initiation and progression. Targeting oncogenic signals elicited by RON or its variants by special antibody or small interfering RNA could provide a novel strategy for the treatment of malignant epithelial cancers.
Hangping Yao - One of the best experts on this subject based on the ideXlab platform.
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Preclinical Efficacy of Anti-RON Antibody-Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase.
Molecular Pharmaceutics, 2018Co-Authors: Hangping Yao, Liang Feng, Tian-hao Weng, Sreedhar Reddy Suthe, A.g.m. Mostofa, Linghui Chen, Weilin Wang, Ming-hai WangAbstract:Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody–drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema Domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly...
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Preclinical Efficacy of Anti-RON Antibody–Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase
2018Co-Authors: Hangping Yao, Liang Feng, Tian-hao Weng, Sreedhar Reddy Suthe, A.g.m. Mostofa, Linghui Chen, Weilin Wang, Ming-hai WangAbstract:Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody–drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema Domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies
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Inhibition of MSP-RON signaling pathway in cancer cells by a novel soluble form of RON comprising the entire Sema sequence
International Journal of Oncology, 2010Co-Authors: Kun Zhang, Hangping Yao, Yong-qing Zhou, Snehal S Padhye, Ming-hai WangAbstract:The RON receptor tyrosine kinase and its ligand macrophage stimulating protein (MSP) play a role in epithelial tumorigenesis. We report here a novel RON variant that antagonizes the RON-MSP pathway in various cancer cells. The variant is an 85 kDa soluble protein from an mRNA transcript with an insertion of 49 nucleotides between exons 5 and 6. The insertion created a stop codon leading to the formation of a RON variant consisting of the entire 35 kDa alpha-chain and a 45 kDa partial extracellular beta-chain. The protein was featured by a Sema Domain, a hinge motif and a portion of the first IPT unit (designated as RONDelta85). RONDelta85 binds directly to MSP, forms MSP-RONDelta85 complex, and inhibits RON phosphorylation. RONDelta85 disrupts RON or RONDelta160 dimerization, prevents their phosphorylation, and attenuates downstream signaling events. The action of RONDelta85 is specific to RON and has no effect on MET and EGFR. In colon and pancreatic cancer cells, RONDelta85 inhibits spontaneous or MSP-induced Erk1/2 and AKT phosphorylation, which results in impaired cell proliferation and colony formation. RONDelta85 also inhibits spontaneous and MSP-induced cell migration. We conclude that RONDelta85 is an antagonist to the MSP-RON pathway, which has potential for regulating RON/RON160-mediated tumorigenic activities.
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Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets.
Cancer Letters, 2007Co-Authors: Hangping Yao, Ming-hai WangAbstract:Abstract Aberrant expression of the RON (Recepteur d’Origine Nantais) receptor tyrosine kinase, accompanied by generation of multiple splicing or truncated variants, contributes to pathogenesis of epithelial cancers. Currently, six variants including RONΔ170, Δ165, Δ160, Δ155, Δ110, and Δ55 with various deletions or truncations in the extracellular or intracellular regions have been identified. The extracellular sequences contain functional structures such as Sema Domain, PSI motif, and IPT units. The deletion or truncation results in constitutive phosphorylation and increased kinase activities. Oncogenic RONΔ160, generated by exclusion of the first IPT unit, is a typical example. In contrast, the deletion adjacent to the conserved MET 1254 in the kinase Domain converts RON into a dominant negative agent. Among three mechanisms underlying isoform production, the switch from constitutive to alternative pre-mRNA splicing is the major event in producing RON variants in cancer cells. Most of the RON variants have the ability to activate multiple signaling cascades with a different substrate specificity and phosphorylation profile. They regulate cell migration, invasion, and proliferation, which contribute to the invasive phenotype and promote the malignant progression. Thus, determining the pathogenesis of RON variants is critical in understanding the mechanisms underlying cancer initiation and progression. Targeting oncogenic signals elicited by RON or its variants by special antibody or small interfering RNA could provide a novel strategy for the treatment of malignant epithelial cancers.
Joëlle Roche - One of the best experts on this subject based on the ideXlab platform.
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Sema3F (Sema Domain, immunoglobulin Domain (Ig), short basic Domain, secreted, (Semaphorin) 3F)
Atlas of genetics and cytogenetics in oncology and haematology, 2011Co-Authors: Vincent Potiron, Harry A. Drabkin, Joëlle RocheAbstract:Review on Sema3F (Sema Domain, immunoglobulin Domain (Ig), short basic Domain, secreted, (Semaphorin) 3F), with data on DNA, on the protein encoded, and where the gene is implicated.
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Redundant functions but temporal and regional regulation of two alternatively spliced isoforms of Semaphorin 3F in the nervous system.
Molecular and Cellular Neuroscience, 2003Co-Authors: Sophie Kusy, Joëlle Roche, Lydiane Funkelstein, David Bourgais, Harry Drabkin, Geneviève Rougon, Valérie CastellaniAbstract:Sema3F is a secreted Semaphorin that affects axon and cell guidance in the developing nervous system, and is also thought to have anti-tumor activity. Two spliced forms of Sema3F have been identified that differ by the insertion of 31 amino acids in the Sema Domain. Here, we investigated the bioactivity of these isoforms and show, using coculture and binding assays, that they share common axonal chemorepulsive properties and binding to neuropilin receptors. Sema3F isoforms were also found to regulate endothelial cell morphology by remodeling lamellipodial protrusions. Although Sema3F expression globally decreased during mouse development, we noted an enrichment of the longest isoform at postnatal stages in some territories such as the brainstem and spinal cord. These results indicate that although functionally redundant in cell culture assays, Sema3F spliced forms are characterized in vivo by a temporal and regional specific regulation during maturation of the nervous system.
Osnat Herzberg - One of the best experts on this subject based on the ideXlab platform.
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Crystal Structure of the Sema-PSI Extracellular Domain of Human RON
2016Co-Authors: Receptor Tyrosine Kinase, Kinlin L. Chao, I-wei Tsai, Chen Chen, Osnat HerzbergAbstract:Human RON (Recepteur d’Origine Nantais) receptor tyrosine kinase is a cell surface receptor for Macrophage Stimulating Protein (MSP). RON mediates signal transduction pathways that regulate cell adhesion, invasion, motility and apoptosis processes. Elevated levels of RON and its alternatively spliced variants are implicated in the progression and metastasis of tumor cells. The binding of MSP a/b heterodimer to the extracellular region of RON receptor induces receptor dimerization and activation by autophosphorylation of the intracellular kinase Domains. The ectoDomain of RON, containing the ligand recognition and dimerization Domains, is composed of a Semaphorin (Sema), Plexins-Semaphorins-Integrins Domain (PSI), and four Immunoglobulins-Plexins-Transcription factor (IPT) Domains. High affinity association between MSP and RON is mediated by the interaction between MSP b-chain and RON Sema, although RON activation requires intact RON and MSP proteins. Here, we report the structure of RON Sema-PSI Domains at 1.85 A ̊ resolution. RON Sema Domain adopts a seven-bladed b-propeller fold, followed by disulfide bond rich, cysteine-knot PSI motif. Comparison with the homologous Met receptor tyrosine kinase reveals that RON Sema-PSI contains distinguishing secondary structural features. These define the receptors ’ exclusive selectivity towards their respective ligands, RON for MSP and Met for HGF. The RON Sema-PSI crystal packing generates a homodimer with interface formed by the Sema Domain. Mapping of the dimer interface using the RON homology to Met, MSP homology to Hepatocyte Growth Factor (HGF), and the structure of the Met/HGF complex shows th
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Crystal structure of the Sema-PSI extracellular Domain of human RON receptor tyrosine kinase.
PLOS ONE, 2012Co-Authors: Kinlin L. Chao, I-wei Tsai, Chen Chen, Osnat HerzbergAbstract:Human RON (Recepteur d’Origine Nantais) receptor tyrosine kinase is a cell surface receptor for Macrophage Stimulating Protein (MSP). RON mediates signal transduction pathways that regulate cell adhesion, invasion, motility and apoptosis processes. Elevated levels of RON and its alternatively spliced variants are implicated in the progression and metastasis of tumor cells. The binding of MSP a/b heterodimer to the extracellular region of RON receptor induces receptor dimerization and activation by autophosphorylation of the intracellular kinase Domains. The ectoDomain of RON, containing the ligand recognition and dimerization Domains, is composed of a Semaphorin (Sema), Plexins-Semaphorins-Integrins Domain (PSI), and four Immunoglobulins-Plexins-Transcription factor (IPT) Domains. High affinity association between MSP and RON is mediated by the interaction between MSP b-chain and RON Sema, although RON activation requires intact RON and MSP proteins. Here, we report the structure of RON Sema-PSI Domains at 1.85 A u resolution. RON Sema Domain adopts a sevenbladed b-propeller fold, followed by disulfide bond rich, cysteine-knot PSI motif. Comparison with the homologous Met receptor tyrosine kinase reveals that RON Sema-PSI contains distinguishing secondary structural features. These define the receptors’ exclusive selectivity towards their respective ligands, RON for MSP and Met for HGF. The RON Sema-PSI crystal packing generates a homodimer with interface formed by the Sema Domain. Mapping of the dimer interface using the RON homology to Met, MSP homology to Hepatocyte Growth Factor (HGF), and the structure of the Met/HGF complex shows the dimer interface overlapping with the putative MSPb binding site. The crystallographically determined RON Sema-PSI homodimer may represent the dimer assembly that occurs during ligand-independent receptor activation and/or the inhibition of the constitutive activity of ROND160 splice variant by the soluble RON splice variant, ROND85.
E Y Jones - One of the best experts on this subject based on the ideXlab platform.
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Diversity of oligomerization in Drosophila Semaphorins suggests a mechanism of functional fine-tuning.
Nature Communications, 2019Co-Authors: D. Rozbesky, Karl Harlos, R.a. Robinson, V. Jain, Max Renner, Tomas Malinauskas, Christian Siebold, E Y JonesAbstract:Semaphorin ligands and their plexin receptors are one of the major cell guidance factors that trigger localised changes in the cytoskeleton. Binding of Semaphorin homodimer to plexin brings two plexins in close proximity which is a prerequisite for plexin signalling. This model appears to be too simplistic to explain the complexity and functional versatility of these molecules. Here, we determine crystal structures for all members of Drosophila class 1 and 2 Semaphorins. Unlike previously reported Semaphorin structures, Sema1a, Sema2a and Sema2b show stabilisation of Sema Domain dimer formation via a disulfide bond. Unexpectedly, our structural and biophysical data show Sema1b is a monomer suggesting that Semaphorin function may not be restricted to dimers. We demonstrate that Semaphorins can form heterodimers with members of the same Semaphorin class. This heterodimerization provides a potential mechanism for cross-talk between different plexins and co-receptors to allow fine-tuning of cell signalling. Semaphorin-plexin interactions regulate various developmental processes in Drosophila but the structural basis of these signaling events is unclear. Here, the authors present crystal structures of all Drosophila class 1 and 2 Semaphorins, and elucidate determinants for their plexin binding specificities.
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Understanding cell signalling systems: paving the way for new therapies
Philosophical Transactions of the Royal Society A, 2015Co-Authors: E Y JonesAbstract:The cell-to-cell signalling mechanisms of multi-cellular organisms orchestrate human development during embryogenesis and control homeostasis in adult tissues. These are mechanisms vital to human health and perturbation of cell-to-cell signalling is a contributing factor in many pathologies including cancer. The Semaphorin cell guidance cues and their cognate plexin receptors exemplify a cell-to-cell signalling system for which insights into mechanistic principles are emerging. X-ray crystallographic data from Diamond beam lines have enabled us to probe the inner workings of Semaphorin–plexin signalling to atomic-level resolutions. Importantly, we can complement protein crystallographic results with biophysical and cellular studies to dovetail structural information with functional impact. The signature seven-bladed β propeller ‘Sema’ Domain of the Semaphorins forms a dimer; in contrast the equivalent Domain in the plexins is monomeric. The generic architecture of a Semaphorin–plexin complex is characterized by the dimeric Semaphorin cross-linking two copies of the plexin receptor. For specific family members, the co-receptor neuropilin serves to bolster this architecture, but in all cases, the dimeric interaction lies at the core of the ligand receptor complex, providing the essential trigger for signalling.
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Structure determination of human Semaphorin 4D as an example of the use of MAD in non-optimal cases.
Acta Crystallographica Section D-biological Crystallography, 2005Co-Authors: Robert Esnouf, Karl Harlos, Christopher Love, David I. Stuart, E Y JonesAbstract:Semaphorins are an important class of signalling molecules involved in axon guidance, immune function and angiogenesis. They are characterized by having an extracellular Sema Domain of about 500 residues. The steps involved in the determination of the structure of human Semaphorin 4D are described here as a case study of selenium MAD phasing in a difficult case with low symmetry, moderate diffraction and low selenium content. A particular feature of this study was the large number of diffraction images required to give data of sufficient quality for structure determination and these data are re-analyzed here to investigate the effects of radiation damage on eventual data quality and to suggest strategies for successful MAD phasing in similar difficult cases.
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The Sema Domain.
Current Opinion in Structural Biology, 2004Co-Authors: Ermanno Gherardi, Christopher Love, Robert Esnouf, E Y JonesAbstract:The Sema Domain was first defined from sequence by Kolodkin and colleagues in the early 1990s, and constitutes the distinctive structural and functional element of Semaphorins, their plexin receptors and the receptor tyrosine kinases MET and RON, three protein families with major roles in development, tissue regeneration and cancer. Recently determined crystal structures of two Semaphorins (Sema3A and Sema4D) and the MET receptor have shown that the Sema Domain consists of a highly conserved variant form of the seven-blade beta-propeller fold. The structures, however, also suggest differences between these families with respect to the mode of dimerisation and the regions of the Domain involved in ligand-receptor interactions. This reflects the considerable plasticity and adaptation of the Sema Domain in order to meet different binding requirements, properties that may underlie the vast array of ligand-receptor specificities and functions of the Semaphorin superfamily.