Premium
Classifying protein kinase structures guides use of ligand‐selectivity profiles to predict inactive conformations: Structure of lck/imatinib complex
Author(s) -
Jacobs Marc D.,
Caron Paul R.,
Hare Brian J.
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21633
Subject(s) - kinase , chemistry , proto oncogene tyrosine protein kinase src , selectivity , imatinib , abl , biochemistry , stereochemistry , computational biology , signal transduction , biology , cancer research , tyrosine kinase , catalysis , myeloid leukemia
We report a clustering of public human protein kinase structures based on the conformations of two structural elements, the activation segment and the C‐helix, revealing three discrete clusters. One cluster includes kinases in catalytically active conformations. Each of the other clusters contains a distinct inactive conformation. Typically, kinases adopt at most one of the inactive conformations in available X‐ray structures, implying that one of the conformations is preferred for many kinases. The classification is consistent with selectivity profiles of several well‐characterized kinase inhibitors. We show further that inhibitor selectivity profiles guide kinase classification. For example, selective inhibition of lck among src‐family kinases by imatinib (Gleevec) suggests that the relative stabilities of inactive conformations of lck are different from other src‐family kinases. We report the X‐ray structure of the lck/imatinib complex, confirming that the conformation adopted by lck is distinct from other structurally‐characterized src‐family kinases and instead resembles kinases abl1 and kit in complex with imatinib. Our classification creates new paths for designing small‐molecule inhibitors. Proteins 2008. © 2007 Wiley‐Liss, Inc.