Homology modelling of human CYP2E1 based on the CYP2C5 crystal structure: Investigation of enzyme-substrate and enzyme-inhibitor interactions
article
The construction of a homology model of human cytochrome P450 2E1 (CYP2E1) is reported, based on the CYP2C5 crystallographic template. A relatively high degree of primary sequence homology (identity=59%), as expected for proteins of the same CYP family, ensured a straightforward generation of the 3-dimensional model due to relatively few deletions and insertions of amino acid residues with respect to the CYP2C5 crystal structure. Probing the CYP2E1 model with typical substrates of the enzyme showed a good agreement with experimental information in the form of positions of metabolism for substrates, and with site-directed mutagenesis data on certain residues. Furthermore, quantitative relationships between substrate binding affinity and various structural parameters associated with the substrate molecules facilitated the formulation of a procedure for estimating relative binding energy and, consequently, K<sub>m</sub> or K<sub>D</sub> values towards the CYP2E1 enzyme. This method has been based on a consideration of the active site interactions between substrates and key amino acid residues lining the haem pocket, together with compound lipophilicity data from partition coefficients. © 2002 Elsevier Science Ltd. All rights reserved. Chemicals/CAS: Cytochrome P-450 CYP2E1, EC 1.14.14.1
Topics
Cytochromes P450(CYP)Human CYP2E1 enzymeMolecular modellingcytochrome P450 2Ccytochrome P450 2C5cytochrome P450 2E1enzyme inhibitorunclassified drugbinding affinitycrystal structurecrystallographyenergyenzyme substratelipophilicitymetabolismmutagenesisprotein familysequence homologyAmino Acid SequenceCrystallizationCytochrome P-450 CYP2E1HumansModels, MolecularMolecular Sequence DataSequence Alignment
TNO Identifier
280280
ISSN
08872333
Source
Toxicology in Vitro, 17(1), pp. 93-105.
Pages
93-105
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