Publication Date:
2015-02-24
Description:
Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405104/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405104/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, C -- Agafonov, R V -- Hoemberger, M -- Kutter, S -- Zorba, A -- Halpin, J -- Buosi, V -- Otten, R -- Waterman, D -- Theobald, D L -- Kern, D -- GM094468/GM/NIGMS NIH HHS/ -- GM096053/GM/NIGMS NIH HHS/ -- GM100966-01/GM/NIGMS NIH HHS/ -- R01 GM094468/GM/NIGMS NIH HHS/ -- R01 GM096053/GM/NIGMS NIH HHS/ -- R01 GM100966/GM/NIGMS NIH HHS/ -- T32 EB009419/EB/NIBIB NIH HHS/ -- T32 GM007596/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):882-6. doi: 10.1126/science.aaa1823.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. ; Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. ; Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. dkern@brandeis.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700521" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Agents/chemistry/*pharmacology
;
Benzamides/chemistry/*pharmacology
;
Drug Resistance, Neoplasm/*genetics
;
Entropy
;
*Evolution, Molecular
;
Humans
;
Imatinib Mesylate
;
Mutation
;
Oncogene Proteins v-abl/chemistry/genetics
;
Phylogeny
;
Piperazines/chemistry/*pharmacology
;
Protein Binding
;
Protein Kinase Inhibitors/chemistry/*pharmacology
;
Protein Structure, Secondary
;
Pyrimidines/chemistry/*pharmacology
;
src-Family Kinases/*chemistry/classification/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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