Homology Model of Human Retinoic Acid Metabolising Enzyme Cytochrome P450 26A1 (CYP26A1): Active Site Architecture and Ligand Binding

Gomaa, Mohamed Sayed, Yee, Sook Wah, Milbourne, Ceri Elizabeth, Barbera, Maria Chiara, Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 and Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 2006. Homology Model of Human Retinoic Acid Metabolising Enzyme Cytochrome P450 26A1 (CYP26A1): Active Site Architecture and Ligand Binding. Journal of Enzyme Inhibition and Medicinal Chemistry 21 (4) , pp. 361-369. 10.1080/14756360600742014

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Abstract

Homology models of cytochrome P450 RA1 (CYP26A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using MOE software the lowest energy CYP26A1 model was then assessed for stereochemical quality and side chain environment. Further active site optimisation of the CYP26A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP26A1 model. The natural substrate, all-trans-retinoic acid (atRA), and inhibitor R115866, were docked into the model allowing further validation of the active site architecture. Using the docking studies structurally and functionally important residues were identified with subsequent characterisation of secondary structure. Multiple hydrophobic interactions, including the side chains of TRP112, PHE299, PHE222, PHE84, PHE374 and PRO371, are important for binding of atRA and R115866. Additional hydrogen bonding interactions were noted as follows: atRA – CvO of the atRA carboxylate group and ARG86; R115866 – benzothiazole nitrogen and the backbone NH of SER115.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords:	CYP26A1 ; homology model ; MOE ; all-trans-retinoic acid (atRA) ; docking studies ; inhibitor interactions ; inhibition ; R115866.
ISSN:	1475-6374
Last Modified:	05 Jan 2024 05:57
URI:	https://orca.cardiff.ac.uk/id/eprint/7438

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