title: Microsecond molecular dynamics simulations provide insight into the ATP-competitive inhibitor-induced allosteric protection of Akt kinase phosphorylation.
abstract: Akt is a serine/threonine protein kinase, a critical mediator of growth factor-induced survival in key cellular pathways. Allosteric signaling between protein intramolecular domains requires long-range communication mediated by hotspot residues, often triggered by ligand binding. Here, based on extensive 3 μs explicit solvent molecular dynamics (MD) simulations of Akt1 kinase domain in the unbound (apo) and ATP-competitive inhibitor, GDC-0068-bound states, we propose a molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by GDC-0068 binding to the ATP-binding site. MD simulations revealed that the apo Akt1 is flexible with two disengaged N- and C-lobes, equilibrated between the open and closed conformations. GDC-0068 occupancy of the ATP-binding site shifts the conformational equilibrium of Akt1 from the open conformation toward the closed conformation and stabilizes the closed state. This effect enables allosteric signal propagation from the GDC-0068 to the phosphorylated T308 (pT308) in the activation loop and restrains phosphatase access to pT308, thereby protecting the pT308 in the GDC-0068-bound Akt1. Importantly, functional hotspots involved in the allosteric communication from the GDC-0068 to the pT308 are identified. Our analysis of GDC-0068-induced allosteric protection of Akt kinase phosphorylation yields important new insights into the molecular mechanism of allosteric regulation of Akt kinase activity.
authors: Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China.
authors: Linkai
authors: L
authors: Mou
authors: Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China.
authors: Tongwei
authors: T
authors: Cui
authors: Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China.
authors: Weiguang
authors: W
authors: Liu
authors: Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China.
authors: Hong
authors: H
authors: Zhang
authors: Department of Electrical and Computer Engineering, College of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
authors: Zhanxiu
authors: Z
authors: Cai
authors: Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Shaoyong
authors: S
authors: Lu
authors: Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China.
authors: Guojun
authors: G
authors: Gao
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D001665:Binding Sites; D001667:Binding, Competitive; D020134:Catalytic Domain; D006801:Humans; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D025341:Principal Component Analysis; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C583616:ipatasertib; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt
keywords: GDC-0068; allosteric communication; allosteric effects; allosteric regulation; allostery; hotspots