title: A dynamic view of ATP-coupled functioning cycle of Hsp90 N-terminal domain.
abstract: Heat-shock protein 90 (Hsp90) is one of the most important chaperones involved in multiple cellular processes. The chaperoning function of Hsp90 is intimately coupled to the ATPase activity presented by its N-terminal domain. However, the molecular mechanism for the ATP-dependent working cycle of Hsp90 is still not fully understood. In this study, we use NMR techniques to investigate the structural characteristics and dynamic behaviors of Hsp90 N-terminal domain in its free and AMPPCP (ATP analogue) or ADP-bound states. We demonstrated that although AMPPCP and ADP bind to almost the same region of Hsp90, significantly different effects on the dynamics behaviors of the key structural elements were observed. AMPPCP binding favors the formation of the active homodimer of Hsp90 by enhancing the slow-motion featured conformational exchanges of those residues (A117-A141) within the lid segment (A111-G135) and around region, while ADP binding keeps Hsp90 staying at the inactive state by increasing the conformational rigidity of the lid segment and around region. Based on our findings, a dynamic working model for the ATP-dependent functioning cycle of Hsp90 was proposed.
authors: Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Huaqun
authors: H
authors: Zhang
authors: Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Chen
authors: C
authors: Zhou
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Wuyan
authors: W
authors: Chen
authors: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Yechun
authors: Y
authors: Xu
authors: Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Yanhong
authors: Y
authors: Shi
authors: Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Yi
authors: Y
authors: Wen
authors: 1] Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China [2] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors: Naixia
authors: N
authors: Zhang
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013816:Thermodynamics
chemical_list: D018841:HSP90 Heat-Shock Proteins; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate