Molecular modeling and identification of substrate binding site of orphan human cytochrome P450 4F22

Kumar, Suresh
September 2011
Bioinformation;2011, Vol. 7 Issue 4, p207
Academic Journal
Cytochrome P450s are superfamily of heme proteins which generally monooxygenate hydrophobic compounds. The human cytochrome P450 4F22 (CYP4F22) was categorized into "orphan" CYPs because of its unknown function. CYP4F22 is a potential drug target for cancer therapy. However, three-dimensional structure, the active site topology and substrate specificity of CYP4F22 remain unclear. In this study, a three-dimensional model of human P450 4F22 was constructed by comparative modeling using Modeller 9v5. The resulting model was refined by energy minimization, subjected to the quality assessment from both geometric and energetic aspects and was found to be of reasonable quality. Docking approach was employed to dock arachidonic acid into the active site of CYP4F22 in order to probe the ligand-binding modes. As a result, several key residues were identified to be responsible for the binding of arachidonic acid with CYP4F22. These findings provide useful information for understanding the biological roles of CYP4F22 and structure-based drug design.


Related Articles

  • Is There a Relationship Between the Substrate Preferences and Structural Flexibility of Cytochromes P450? Otyepka, Michal; Berka, Karel; Anzenbacher, Pavel // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p130 

    In the last decades, the structural flexibility of cytochromes P450 has been extensively studied by spectroscopic and in silico methods. Here, both approaches are reviewed and compared. Comparison of both methods indicates that the individual cytochromes P450 differ significantly in the...

  • Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. Oostenbrink, Chris; De Ruiter, Anita; Hritz, Jozef; Vermeulen, Nico // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p190 

    As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show...

  • Molecular Surface Representation Using 3D Zernike Descriptors for Protein Shape Comparison and Docking. Kihara, Daisuke; Sael, Lee; Chikhi, Rayan; Esquivel-Rodriguez, Juan // Current Protein & Peptide Science;Sep2011, Vol. 12 Issue 6, p520 

    The tertiary structures of proteins have been solved in an increasing pace in recent years. To capitalize the enormous efforts paid for accumulating the structure data, efficient and effective computational methods need to be developed for comparing, searching, and investigating interactions of...

  • Molecular modeling of mammalian cytochrome P450s. Dai, R.; Pincus, M. R.; Friedman, F. K. // Cellular & Molecular Life Sciences;Mar2000, Vol. 57 Issue 3, p487 

    The cytochrome P450s are a superfamily of hemoprotein enzymes responsible for the metabolism of a wide variety of xenobiotic and endogenous compounds. The individual P450s exhibit unique substrate specificity and stereoselectivity profiles which reflect corresponding differences in primary...

  • Comparative modeling and molecular docking of orphan human CYP4V2 protein with fatty acid substrates: Insights into substrate specificity. Kumar, Suresh // Bioinformation;2011, Vol. 7 Issue 7, p360 

    Cytochromes P450 (CYPs) are a super family of heme-containing enzymes well-known for their monooxgenase reaction. There are 57 CYP isoenzymes found in human which exhibit specific physiological functions. Thirteen members of this super family are classified as "orphan" CYP because of their...

  • Plasticity of CYP2B Enzymes: Structural and Solution Biophysical Methods. Wilderman, P. Ross; Halpert, James R. // Current Drug Metabolism;Feb2012, Vol. 13 Issue 2, p167 

    In the past three years, major advances in understanding cytochrome P450 2B (CYP2B) structure-function relationships have been made through determination of multiple ligand-bound and one ligand-free X-ray crystal structure of CYP2B4 and one ligand-bound X-ray crystal structure of CYP2B6. These...

  • A Hierarchical Approach to Cooperativity in Macromolecular and Self-Assembling Binding Systems. Garc�s, Josep; Acerenza, Luis; Mizraji, Eduardo; Mas, Francesc // Journal of Biological Physics;Jan2008, Vol. 34 Issue 1/2, p213 

    The study of complex macromolecular binding systems reveals that a high number of states and processes are involved in their mechanism of action, as has become more apparent with the sophistication of the experimental techniques used. The resulting information is often difficult to interpret...

  • Ligands bind to Sortilin in the tunnel of a ten-bladed β-propeller domain. Quistgaard, Esben M.; Madsen, Peder; Grøftehauge, Morten K.; Nissen, Poul; Petersen, Claus M.; Thirup, Søren S. // Nature Structural & Molecular Biology;Jan2009, Vol. 16 Issue 1, p96 

    The structure of the Sortilin ectodomain in complex with neurotensin has been determined at 2-Å resolution, revealing that the C-terminal part of neurotensin binds in the tunnel of a ten-bladed β-propeller domain. Binding competition studies suggest that additional binding sites, for...

  • Catalytic residues in hydrolases: analysis of methods designed for ligand-binding site prediction. Prymula, Katarzyna; Jadczyk, Tomasz; Roterman, Irena // Journal of Computer-Aided Molecular Design;Feb2011, Vol. 25 Issue 2, p117 

    The comparison of eight tools applicable to ligand-binding site prediction is presented. The methods examined cover three types of approaches: the geometrical (CASTp, PASS, Pocket-Finder), the physicochemical (Q-SiteFinder, FOD) and the knowledge-based (ConSurf, SuMo, WebFEATURE). The accuracy...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics