title: Characterization of the interface of the bone marrow stromal cell antigen 2-Vpu protein complex via computational chemistry.
abstract: Bone marrow stromal cell antigen 2 (BST-2) inhibits the release of enveloped viruses from the cell surface. Various viral counter measures have been discovered, which allow viruses to escape BST-2 restriction. Human immunodeficiency virus type 1 (HIV-1) encodes viral protein U (Vpu) that interacts with BST-2 through their transmembrane domains and causes the downregulation of cell surface BST-2. In this study, we used a computer modeling method to establish a molecular model to investigate the binding interface of the transmembrane domains of BST-2 and Vpu. The model predicts that the interface is composed of Vpu residues I6, A10, A14, A18, V25, and W22 and BST-2 residues L23, I26, V30, I34, V35, L41, I42, and T45. Introduction of mutations that have been previously reported to disrupt the Vpu-BST-2 interaction led to a calculated higher binding free energy (MMGBSA), which supports our molecular model. A pharmacophore was also generated on the basis of this model. Our results provide a precise model that predicts the detailed interaction occurring between the transmembrane domains of Vpu and BST-2 and should facilitate the design of anti-HIV agents that are able to disrupt this interaction.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. zhou_jim@hotmail.com
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zeyun
authors.initials: Z
authors.lastname: Mi
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.forename: Shan
authors.initials: S
authors.lastname: Cen
mesh_terms: D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics; D001854:Bone Marrow Cells / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry*; D054298:Human Immunodeficiency Virus Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000235:genetics; D025941:Protein Interaction Mapping; D055503:Protein Multimerization / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017154:Stromal Cells / Q000737:chemistry; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D046912:Multiprotein Complexes; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins