title: Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine.
abstract: CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Å resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of CXCR4. The complex structure reveals binding hot spots for future inhibitor design and suggests a new approach to targeting CXCL12-CXCR4 signaling in drug discovery.
authors.affiliation: Department of Molecular Medicine, University of South Florida , 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
authors.forename: Emmanuel W
authors.initials: EW
authors.lastname: Smith
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Getschman
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Ziarek
authors.forename: Rongshi
authors.initials: R
authors.lastname: Li
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000737:chemistry*; D002633:Chemotaxis; D018360:Crystallography, X-Ray / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000737:chemistry*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D019718:Receptors, CXCR4