Comparative Dynamics and Functional Mechanisms of the CYP17A1 Tunnels Regulated by Ligand Binding.

Journal of Chemical Information and Modeling
Fei XiaoGuang Hu

Abstract

As an important member of cytochrome P450 (CYP) enzymes, CYP17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones, making it an attractive therapeutic target. The emerging structural information about CYP17A1 and the growing number of inhibitors for these enzymes call for a systematic strategy to delineate and classify mechanisms of ligand transport through tunnels that control catalytic activity. In this work, we applied an integrated computational strategy to different CYP17A1 systems with a panel of ligands to systematically study at the atomic level the mechanism of ligand-binding and tunneling dynamics. Atomistic simulations and binding free energy computations identify the dynamics of dominant tunnels and characterize energetic properties of critical residues responsible for ligand binding. The common transporting pathways including S, 3, and 2c tunnels were identified in CYP17A1 binding systems, while the 2c tunnel is a newly formed pathway upon ligand binding. We employed and integrated several computational approaches including the analysis of functional motions and sequence conservation, atomistic modeling of dynamic residue interaction networks, and perturbation re...Continue Reading

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