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Theoretical Characterization of Substrate Access/Exit Channels in the Human Cytochrome P450 3A4 Enzyme: Involvement of Phenylalanine Residues in the Gating Mechanism

  1. Author:
    Fishelovitch, D.
    Shaik, S.
    Wolfson, H. J.
    Nussinov, R.

  2. Author Address

    Nussinov, Ruth] NCI, CCRNB, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Fishelovitch, Dan, Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel. [Wolfson, Haim J.] Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel.
    1. Year: 2009
  2. Journal: Journal of Physical Chemistry B
    1. 113
    2. 39
    3. Pages: 13018-13025
  4. Type of Article: Article
  1. Abstract:

    The human cytochrome P450 3A4 mono-oxygenates similar to 50% of all drugs. Its substrates/products enter/leave the active site by access/exit channels. Here, we perform steered molecular dynamics simulations, pulling the products temazepam and testosterone-6 beta OH out of the P450 3A4 enzyme in order to identify the preferred substrate/product pathways and their gating mechanism. We locate six different egress pathways of products from the active site with different exit preferences for the two products and find that there is more than just one access/exit channel in CYP3A4. The so-called solvent channel manifests the largest opening for both tested products, thereby identifying this channel as a putative substrate channel. Most channels consist of one or two pi-stacked pherylalanine residues that serve as gate keepers. The oxidized drug breaks the hydrophobic interactions of the gating residues and forms mainly hydrophobic contacts with the gate. We argue that product exit preferences in P450s are regulated by protein-substrate specificity.

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  2. DOI: 10.1021/jp810386z
  3. PMID: 19728720

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