{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T15:53:22Z","timestamp":1761580402022},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: According to the models of divergent molecular evolution, the evolvability of new protein function may depend on the induction of new phenotypic traits by a small number of mutations of the binding site residues. Evolutionary relationships between protein kinases are often employed to infer inhibitor binding profiles from sequence analysis. However, protein kinases binding profiles may display inhibitor selectivity within a given kinase subfamily, while exhibiting cross-activity between kinases that are phylogenetically remote from the prime target. The emerging insights into kinase function and evolution combined with a rapidly growing number of publically available crystal structures of protein kinases complexes have motivated structural bioinformatics analysis of sequence\u2013structure relationships in determining the binding function of protein tyrosine kinases.<\/jats:p>\n               <jats:p>Results: \u00a0In silico profiling of Imatinib mesylate and PD-173955 kinase inhibitors with protein tyrosine kinases is conducted on kinome scale by using evolutionary analysis and fingerprinting inhibitor\u2013protein interactions with the panel of all publically available protein tyrosine kinases crystal structures. We have found that sequence plasticity of the binding site residues alone may not be sufficient to enable protein tyrosine kinases to readily evolve novel binding activities with inhibitors. While evolutionary signal derived solely from the tyrosine kinase sequence conservation can not be readily translated into the ligand binding phenotype, the proposed structural bioinformatics analysis can discriminate a functionally relevant kinase binding signal from a simple phylogenetic relationship. The results of this work reveal that protein conformational diversity is intimately linked with sequence plasticity of the binding site residues in achieving functional adaptability of protein kinases towards specific drug binding. This study offers a plausible molecular rationale to the experimental binding profiles of the studied kinase inhibitors and provides a theoretical basis for constructing functionally relevant kinase binding trees.<\/jats:p>\n               <jats:p>Contact: \u00a0gverkhiv@ucsd.edu<\/jats:p>\n               <jats:p>Supplementary information: The supplementary material contains the details of the phylogenetic analysis of protein tyrosine kinases, including phylogenetic dendrograms of protein tyrosine kinases based on sequence alignments of the kinases catalytic domain and evolutionary conservation profiles of the binding site residues. This section provides a more detailed description of the Monte Carlo binding simulations, including energetic model and simulated tempering technique generalized for ligand\u2013protein binding dynamics with the multiple protein tyrosine kinase structures.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btl199","type":"journal-article","created":{"date-parts":[[2006,5,24]],"date-time":"2006-05-24T03:34:28Z","timestamp":1148441668000},"page":"1846-1854","source":"Crossref","is-referenced-by-count":12,"title":["Imprint of evolutionary conservation and protein structure variation on the binding function of protein tyrosine kinases"],"prefix":"10.1093","volume":"22","author":[{"given":"Gennady M.","family":"Verkhivker","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California San Diego \u00a0 9500 Gilman Drive, La Jolla, CA 92093-0392, USA"}]}],"member":"286","published-online":{"date-parts":[[2006,5,23]]},"reference":[{"key":"2023012409121785700_b1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/ng1482","article-title":"The \u2018evolvability\u2019 of promiscuous protein functions","volume":"37","author":"Aharoni","year":"2005","journal-title":"Nature Genet."},{"key":"2023012409121785700_b2","doi-asserted-by":"crossref","first-page":"55827","DOI":"10.1074\/jbc.M409792200","article-title":"A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase","volume":"279","author":"Atwell","year":"2004","journal-title":"J. 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