Theoretical characterization of substrate access/exit channels in the human cytochrome P450 3A4 enzyme: involvement of phenylalanine residues in the gating mechanism

Dan Fishelovitch, Sason Shaik, Haim J. Wolfson, Ruth Nussinov

Research output: Contribution to journalArticlepeer-review

Abstract

The human cytochrome P450 3A4 mono-oxygenates ∼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-6/30H 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 π-stacked phenylalanine 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.

Original languageEnglish
Pages (from-to)13018-13025
Number of pages8
JournalJournal of Physical Chemistry B
Volume113
Issue number39
DOIs
StatePublished - 1 Oct 2009

Fingerprint

Dive into the research topics of 'Theoretical characterization of substrate access/exit channels in the human cytochrome P450 3A4 enzyme: involvement of phenylalanine residues in the gating mechanism'. Together they form a unique fingerprint.

Cite this