title: Structural analysis of a novel rabbit monoclonal antibody R53 targeting an epitope in HIV-1 gp120 C4 region critical for receptor and co-receptor binding.
abstract: The fourth conserved region (C4) in the HIV-1 envelope glycoprotein (Env) gp120 is a structural element that is important for its function, as it binds to both the receptor CD4 and the co-receptor CCR5/CXCR4. It has long been known that this region is highly immunogenic and that it harbors B-cell as well as T-cell epitopes. It is the target of a number of antibodies in animal studies, which are called CD4-blockers. However, the mechanism by which the virus shields itself from such antibody responses is not known. Here, we determined the crystal structure of R53 in complex with its epitope peptide using a novel anti-C4 rabbit monoclonal antibody R53. Our data show that although the epitope of R53 covers a highly conserved sequence (433)AMYAPPI(439), it is not available in the gp120 trimer and in the CD4-bound conformation. Our results suggest a masking mechanism to explain how HIV-1 protects this critical region from the human immune system.
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine , New York, NY 10016, USA.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Pan
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA 01605, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA 01605, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Vaine
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA 01605, USA.
authors.forename: Guangnan
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA 01605, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA 01605, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, New York University School of Medicine , New York, NY 10016, USA.
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000276:immunology; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D003460:Crystallization; D000939:Epitopes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000302:isolation & purification / Q000378:metabolism; D011817:Rabbits; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D012756:Sheep
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: C4; CD4; Env; HIV-1; monoclonal antibody