title: Modeling studies on the structural determinants for the DAG/phorbol ester binding to C1 domain.
abstract: C1 domains are small zinc-binding structural units of approximately 50 amino acids, originally discovered as lipid-binding modules in protein kinase C (PKC) isoforms. C1 domains that bind and respond to the DAG/phorbol ester are termed as typical, and those that do not respond to DAG/phorbol ester are termed as atypical. To design molecules targeting a specific C1 domain for regulating a specific disease state, it is important to understand the factors that make a C1 domain responsive to DAG/phorbol ester. Here, we determined the volume and surface area of the ligand-binding site for all known C1 domains. No correlation was found between the volume/surface area of ligand-binding site and the DAG/phorbol ester-binding affinity. Solvated molecular dynamics simulation reveals that the presence of water molecules affects the flexibility of the ligand-binding site. Contributions of the binding site residues, their orientations, and the membrane lipids on the responsiveness of a C1 domain towards DAG/phorbol ester have been discussed.
authors.affiliation: a Department of Pharmacological and Pharmaceutical Sciences , College of Pharmacy, University of Houston , Houston , TX 77204 , USA.
authors.forename: Ghazi M
authors.initials: GM
authors.lastname: Rahman
authors.forename: Joydip
authors.initials: J
authors.lastname: Das
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004075:Diglycerides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation / Q000379:methods; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D010703:Phorbol Esters / Q000737:chemistry* / Q000378:metabolism; D018583:Pliability; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D004075:Diglycerides; D007527:Isoenzymes; D010703:Phorbol Esters; D014867:Water; D011493:Protein Kinase C
keywords: C1 domain; Sybyl; diacylglycerol; molecular dynamics; molecular modeling; phorbol ester; protein kinase C; protomol