title: Homology model of nonmuscle myosin heavy chain IIA and binding mode analysis with its inhibitor blebbistatin.
abstract: Nonmuscle myosin heavy chain IIA (NMMHC IIA, gene code: MYH9) plays a critical role in physiological and pathological functions. A homology model of NMMHC IIA was constructed based on the crystal structure of smooth muscle myosin II. Blebbistatin, a myosin II ATPase inhibitor, had been found to bind to NMMHC IIA with Leu228 as the important amino acid residue and van der Waals contacts as the main force of the interaction. The final complex demonstrated that the destruction of the salt bridge occurred between the Arg204 and Glu427 residues when blebbistatin was present. Molecular dynamic simulation of the complex showed that the binding affinity of blebbistatin to NMMHC IIA was strongly sensitive to the nucleotide binding region and actin binding region. The disturbance of the two regions increased the enhancement of the binding cavity with blebbistatin and resulted in a slightly more expanded conformation in the nucleotide binding region and actin binding region. A combined pharmacophore- and docking-based virtual screening was performed to identify several saponins as potential inhibitors for NMMHC IIA. These findings introduce new insights on the binding mode of blebbistatin and NMMHC IIA and novel leading compounds from natural products for NMMHC IIA-related diseases.
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of TCM, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, People's Republic of China.
authors: Yanni
authors: Y
authors: Lv
authors: Shuai
authors: S
authors: Lu
authors: Tao
authors: T
authors: Lu
authors: Junping
authors: J
authors: Kou
authors: Boyang
authors: B
authors: Yu
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D024507:Nonmuscle Myosin Type IIA / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D024745:Smooth Muscle Myosins / Q000737:chemistry*; D055672:Static Electricity; D040681:Structural Homology, Protein
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; C472645:blebbistatin; D024507:Nonmuscle Myosin Type IIA; D024745:Smooth Muscle Myosins