title: Importance of receptor flexibility in binding of cyclam compounds to the chemokine receptor CXCR4.
abstract: We have elucidated the binding sites of four moncyclam and one bicyclam antagonist AMD3100, in the human chemokine receptor CXCR4. Using the predicted structural models of CXCR4, we have further predicted the binding sites of these cyclam compounds. We used the computational method LITiCon to map the differences in receptor structure stabilized by the mono and bicyclam compounds. Accounting for the receptor flexibility lead to a single binding mode for the cyclam compounds, that has not been possible previously using a single receptor structural model and fixed receptor docking algorithms. There are several notable differences in the receptor conformations stabilized by monocyclam antagonist compared to a bicylam antagonist. The loading of the Cu(2+) ions in the cyclam compounds, shrinks the size of the cyclam rings and the residue D262(6.58) plays an important role in bonding to the copper ion in the monocylam compounds while residue E288(7.39) is important for the bicyclam compound.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Alfonso R
authors.initials: AR
authors.lastname: Lam
authors.forename: Supriyo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Kevin
authors.initials: K
authors.lastname: Patel
authors.forename: Spencer E
authors.initials: SE
authors.lastname: Hall
authors.forename: Allen
authors.initials: A
authors.lastname: Mao
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Vaidehi
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D001596:Benzylamines; D001665:Binding Sites; D003300:Copper / Q000737:chemistry; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; C024560:cyclam; D003300:Copper; C088327:plerixafor