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Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.

Jacobs MD, Caron PR, Hare BJ
Proteins 70 1451-60 (2008)
Cited: 49 times
EuropePMC logo PMID: 17910071

Abstract

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.

Reviews - 2pl0 mentioned but not cited (2)

  1. New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011-2021) focussing on structure-activity relationship (SAR) and docking insights. Elkamhawy A, Ali EMH, Lee K. J Enzyme Inhib Med Chem 36 1574-1602 (2021)
  2. A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature. Lanz AL, Erdem S, Ozcan A, Ceylaner G, Cansever M, Ceylaner S, Conca R, Magg T, Acuto O, Latour S, Klein C, Patiroglu T, Unal E, Eken A, Hauck F. J Clin Immunol 44 1 (2023)

Articles - 2pl0 mentioned but not cited (18)

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  17. Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity. Kalinichenko E, Faryna A, Bozhok T, Golyakovich A, Panibrat A. Curr Issues Mol Biol 45 1820-1842 (2023)
  18. Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors. Kalinichenko E, Faryna A, Bozhok T, Panibrat A. Int J Mol Sci 22 12738 (2021)


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  20. Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR. Takayama T, Umemiya H, Amada H, Yabuuchi T, Koami T, Shiozawa F, Oka Y, Takaoka A, Yamaguchi A, Endo M, Sato M. Bioorg. Med. Chem. Lett. 20 112-116 (2010)
  21. Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase. Gao C, Grøtli M, Eriksson LA. J Mol Model 21 167 (2015)
  22. Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of the Native and Mutated CSF-1R and KIT. Da Silva Figueiredo Celestino Gomes P, Chauvot De Beauchêne I, Panel N, Lopez S, De Sepulveda P, Geraldo Pascutti P, Solary E, Tchertanov L. PLoS ONE 11 e0160165 (2016)
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  24. Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type. Bresso E, Furlan A, Noel P, Leroux V, Maina F, Dono R, Maigret B. Molecules 25 (2020)
  25. Crystal Structures Reveal Hidden Domain Mechanics in Protein Kinase A (PKA). Welsh CL, Conklin AE, Madan LK. Biology (Basel) 12 1370 (2023)
  26. Defining a new nomenclature for the structures of active and inactive kinases. Modi V, Dunbrack RL. Proc. Natl. Acad. Sci. U.S.A. 116 6818-6827 (2019)
  27. Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches. Meganathan C, Sakkiah S, Lee Y, Narayanan JV, Lee KW. J Mol Model 19 715-726 (2013)
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