title: Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists.
abstract: CXCR4 is a G protein-coupled receptor (GPCR) that has multiple critical functions in normal and pathologic physiology that include regulation of the metastatic behavior of mammary carcinoma, and utilization as a coreceptor for infection by T-tropic strains of human immunodeficiency virus-1. Molecular dynamic simulations of the rhodopsin-based homology model of CXCR4 were performed in a solvated lipid bilayer to reproduce the microenvironment of this integral membrane protein. The amino acids in CXCR4 necessary for interaction with an inverse agonist, T140, and a weak partial agonist, AMD3100, identified by alanine scanning mutants, were spatially consistent when computationally docked. Whereas T140 binds residues in extracellular domains and regions of the hydrophobic core proximal to the cell surface, amino acids in the central hydrophobic core are critical to binding of AMD3100. The physical localization of T140 binding to CXCR4 by biochemical analyses corroborated the molecular and computational approaches. The structural basis for the interaction of T140 and AMD3100 with CXCR4 confirms that the mechanisms used by these agents are different. This complementary utilization of molecular, physical, and computation analysis provides a powerful approach to elucidate GPCR conformation.
authors.affiliation: J. G. Brown Modeling Facility, 323 Brown Cancer Center, Department of Medicine, University of Louisville, 529 S. Jackson Street, Louisville, KY 40202, USA. john.trent@louisville.edu
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Zi-xuan
authors.initials: ZX
authors.lastname: Wang
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.forename: Wenhai
authors.initials: W
authors.lastname: Shao
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
mesh_terms: D019943:Amino Acid Substitution; D001596:Benzylamines; D003198:Computer Simulation; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000378:metabolism; D008051:Lipid Bilayers; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D009842:Oligopeptides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008051:Lipid Bilayers; D008565:Membrane Proteins; D009842:Oligopeptides; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; C116977:T140 peptide; C088327:plerixafor