Threading with chemostructural restrictions method for predicting fold and functionally significant residues: application to dipeptidylpeptidase IV (DPP-IV) |
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Authors: | Reva Boris Finkelstein Alexei Topiol Sid |
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Affiliation: | Novartis Institute for Biomedical Research, Summit, New Jersey, USA. breva@stprot.com |
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Abstract: | We present a new method for more accurate modeling of protein structure, called threading with chemostructural restrictions. This method addresses those cases in which a target sequence has only remote homologues of known structure for which sequence comparison methods cannot provide accurate alignments. Although remote homologues cannot provide an accurate model for the whole chain, they can be used in constructing practically useful models for the most conserved-and often the most interesting-part of the structure. For many proteins of interest, one can suggest certain chemostructural patterns for the native structure based on the available information on the structural superfamily of the protein, the type of activity, the sequence location of the functionally significant residues, and other factors. We use such patterns to restrict (1) a number of possible templates, and (2) a number of allowed chain conformations on a template. The latter restrictions are imposed in the form of additional template potentials (including terms acting as sequence anchors) that act on certain residues. This approach is tested on remote homologues of alpha/beta-hydrolases that have significant structural similarity in the positions of their catalytic triads. The study shows that, in spite of significant deviations between the model and the native structures, the surroundings of the catalytic triad (positions of C(alpha) atoms of 20-30 nearby residues) can be reproduced with accuracy of 2-3 A. We then apply the approach to predict the structure of dipeptidylpeptidase IV (DPP-IV). Using experimentally available data identifying the catalytic triad residues of DPP-IV (David et al., J Biol Chem 1993;268:17247-17252); we predict a model structure of the catalytic domain of DPP-IV based on the 3D fold of prolyl oligopeptidase (Fulop et al., Cell 1998;94:161-170) and use this structure for modeling the interaction of DPP-IV with inhibitor. |
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Keywords: | 1qfmA 1din 1qfsA 1eptA 1ivyA 1fssA 2had 1bn6A 1bn7A 1cqwA 1q1wA 1q1wB 1cleA 5lip 1qtrA 2bce 1lps 1cleB 1maaD 1a8s 1jkmA 7yasA 1thtB 1aurB threading with chemostructural restrictions chemostructural invariance α/β‐hydrolases dipeptidylpeptidase IV |
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