Rabbit indolethylamine N-methyltransferase three-dimensional structure prediction: a model approach to bridge sequence to function in pharmacogenomic studies

Abstract.

Pharmacogenomics is the study of the genetic basis for individual variation in response to drugs and other xenobiotics. Successful prediction of effects of genetic variations that change encoded amino acid sequences on protein function and their consequent biomedical implications depends on three-dimensional (3D) structures of the encoded amino acid sequences. To bridge sequence to function, thus facilitating an in-depth pharmacogenomic study, we tested the feasibility of the use of a semi-computational approach to predict 3D structures of rabbit and human indolethylamine N-methyltransferases (INMTs) from their amino acid sequences, which share less than 26% sequence identity with known protein 3D structures. Herein, we report 3D models of INMTs predicted by using the crystal structure of rat catechol O-methyltransferase as a template, testing of the models both computationally and experimentally, and successful use of the models in retrospective prediction of the effects of genetic polymorphisms and in identification of residues that contribute to observed species-specific differences in substrate affinity. The results encourage the use of the semi-computational approach to predict 3D protein structures for use in pharmacogenomic studies when de novo prediction of protein 3D structures from their amino acid sequences is still not feasible and X-ray crystallography and/or solution nuclear magnetic resonance spectroscopy can only determine 3D structures for a small number of known amino acid sequences.