Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity
| Autor: | Irina Kufareva, Tony Ngo, Bryan S. Stephens, Martin Gustavsson, Ruben Abagyan, Tracy M. Handel, Lauren G. Holden |
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| Přispěvatelé: | Bertrand, Mathieu JM |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Chemokine Subfamily Insecta Protein Conformation Geometry CXCR4 Medical and Health Sciences Physical Chemistry Immune Receptors Biochemistry 0302 clinical medicine Protein structure Spectrum Analysis Techniques Models Receptors Cross-Linking Medicine and Health Sciences 2.1 Biological and endogenous factors Disulfides Aetiology Amino Acids Biology (General) Receptor beta-Arrestins Cancer 0303 health sciences Crystallography Immune System Proteins biology Chemistry Blotting Organic Compounds General Neuroscience Chemotaxis Physics 030302 biochemistry & molecular biology Pattern recognition receptor Cell migration Biological Sciences Flow Cytometry Condensed Matter Physics Small molecule 3. Good health Cell Motility Spectrophotometry Physical Sciences Crystal Structure Cytophotometry Chemokines General Agricultural and Biological Sciences Western Research Article Signal Transduction Receptors CXCR4 QH301-705.5 Immunology Blotting Western Therapeutic targeting Research and Analysis Methods General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Rare Diseases Genetics Solid State Physics Sulfur Containing Amino Acids Animals Humans Protein Interaction Domains and Motifs Cysteine 030304 developmental biology Binding Sites General Immunology and Microbiology Agricultural and Veterinary Sciences Chemical Bonding HEK 293 cells Organic Chemistry Rational design Chemical Compounds Molecular Biology and Life Sciences Proteins Hydrogen Bonding Cell Biology Chemokine CXCL12 030104 developmental biology HEK293 Cells Mutagenesis Mutation biology.protein Pattern Recognition Receptors 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology, Vol 18, Iss 4, p e3000656 (2020) PLoS Biology PLoS biology, vol 18, iss 4 |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | Chemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here, we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide cross-linking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 β1-strand, while also recapitulating earlier findings from nuclear magnetic resonance, modeling and crystallography of homologous receptors. A cross-linking–informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor targeting small molecules and biologics with novel pharmacology. An integrated experimental and computational effort produces a consistent and unifying high-resolution model of a receptor-chemokine complex from the CXC subfamily, suggesting previously unknown binding, signaling and selectivity determinants, and filling a critical void in the structural map of an important class of membrane drug targets. |
| Databáze: | OpenAIRE |
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