1yom Citations

Crystal structures of active SRC kinase domain complexes.

J. Mol. Biol. 353 222-31 (2005)
Related entries: 1yol, 1yoj

Cited: 30 times
EuropePMC logo PMID: 16168436


c-Src was the first proto-oncoprotein to be identified, and has become the focus of many drug discovery programs. Src structures of a major inactive form have shown how the protein kinase is rigidified by several interdomain interactions; active configurations of Src are generated by release from this "assembled" or "bundled" form. Despite the importance of Src as a drug target, there is relatively little structural information available regarding the presumably more flexible active forms. Here we report three crystal structures of a dimeric active c-Src kinase domain, in an apo and two ligand complexed forms, with resolutions ranging from 2.9A to 1.95A. The structures show how the kinase domain, in the absence of the rigidifying interdomain interactions of the inactivation state, adopts a more open and flexible conformation. The ATP site inhibitor CGP77675 binds to the protein kinase with canonical hinge hydrogen bonds and also to the c-Src specific threonine 340. In contrast to purvalanol B binding in CDK2, purvalanol A binds in c-Src with a conformational change in a more open ATP pocket.

Articles - 1yom mentioned but not cited (1)

Reviews citing this publication (2)

  1. The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells. Gerbec ZJ, Thakar MS, Malarkannan S. Front Immunol 6 472 (2015)
  2. Protein tyrosine phosphorylation and protein tyrosine nitration in redox signaling. Monteiro HP, Arai RJ, Travassos LR. Antioxid. Redox Signal. 10 843-889 (2008)

Articles citing this publication (27)

  1. Structure-guided development of affinity probes for tyrosine kinases using chemical genetics. Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM. Nat. Chem. Biol. 3 229-238 (2007)
  2. Structural basis for the recognition of c-Src by its inactivator Csk. Levinson NM, Seeliger MA, Cole PA, Kuriyan J. Cell 134 124-134 (2008)
  3. Mapping the conformational transition in Src activation by cumulating the information from multiple molecular dynamics trajectories. Yang S, Banavali NK, Roux B. Proc. Natl. Acad. Sci. U.S.A. 106 3776-3781 (2009)
  4. Src kinase conformational activation: thermodynamics, pathways, and mechanisms. Yang S, Roux B. PLoS Comput. Biol. 4 e1000047 (2008)
  5. Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Piegeler T, Votta-Velis EG, Liu G, Place AT, Schwartz DE, Beck-Schimmer B, Minshall RD, Borgeat A. Anesthesiology 117 548-559 (2012)
  6. Src kinase activation: A switched electrostatic network. Ozkirimli E, Post CB. Protein Sci. 15 1051-1062 (2006)
  7. An electrostatic network and long-range regulation of Src kinases. Ozkirimli E, Yadav SS, Miller WT, Post CB. Protein Sci. 17 1871-1880 (2008)
  8. 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 1451-1460 (2008)
  9. Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity. Lee KM, Lee KW, Jung SK, Lee EJ, Heo YS, Bode AM, Lubet RA, Lee HJ, Dong Z. Biochem. Pharmacol. 80 2042-2049 (2010)
  10. On the importance of a funneled energy landscape for the assembly and regulation of multidomain Src tyrosine kinases. Faraldo-Gómez JD, Roux B. Proc. Natl. Acad. Sci. U.S.A. 104 13643-13648 (2007)
  11. Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds. Dalgarno D, Stehle T, Narula S, Schelling P, van Schravendijk MR, Adams S, Andrade L, Keats J, Ram M, Jin L, Grossman T, MacNeil I, Metcalf C, Shakespeare W, Wang Y, Keenan T, Sundaramoorthi R, Bohacek R, Weigele M, Sawyer T. Chem Biol Drug Des 67 46-57 (2006)
  12. Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors. Ikuta M, Kornienko M, Byrne N, Reid JC, Mizuarai S, Kotani H, Munshi SK. Protein Sci. 16 2626-2635 (2007)
  13. Chemical genetic strategy for targeting protein kinases based on covalent complementarity. Garske AL, Peters U, Cortesi AT, Perez JL, Shokat KM. Proc. Natl. Acad. Sci. U.S.A. 108 15046-15052 (2011)
  14. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. J. Struct. Biol. 165 88-96 (2009)
  15. Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines. Schenone S, Brullo C, Bruno O, Bondavalli F, Mosti L, Maga G, Crespan E, Carraro F, Manetti F, Tintori C, Botta M. Eur J Med Chem 43 2665-2676 (2008)
  16. Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. Radi M, Dreassi E, Brullo C, Crespan E, Tintori C, Bernardo V, Valoti M, Zamperini C, Daigl H, Musumeci F, Carraro F, Naldini A, Filippi I, Maga G, Schenone S, Botta M. J. Med. Chem. 54 2610-2626 (2011)
  17. Purvalanol A, a CDK inhibitor, effectively suppresses Src-mediated transformation by inhibiting both CDKs and c-Src. Hikita T, Oneyama C, Okada M. Genes Cells 15 1051-1062 (2010)
  18. Synthesis and c-Src inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke. Mukaiyama H, Nishimura T, Kobayashi S, Ozawa T, Kamada N, Komatsu Y, Kikuchi S, Oonota H, Kusama H. Bioorg. Med. Chem. 15 868-885 (2007)
  19. Structure-based virtual screening of Src kinase inhibitors. Lee K, Kim J, Jeong KW, Lee KW, Lee Y, Song JY, Kim MS, Lee GS, Kim Y. Bioorg. Med. Chem. 17 3152-3161 (2009)
  20. Mutations in the catalytic loop HRD motif alter the activity and function of Drosophila Src64. Strong TC, Kaur G, Thomas JH. PLoS ONE 6 e28100 (2011)
  21. Rational design of multitargeted tyrosine kinase inhibitors: a novel approach. Barchéchath S, Williams C, Saade K, Lauwagie S, Jean-Claude B. Chem Biol Drug Des 73 380-387 (2009)
  22. Design, synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors. Farard J, Lanceart G, Logé C, Nourrisson MR, Cruzalegui F, Pfeiffer B, Duflos M. J Enzyme Inhib Med Chem 23 629-640 (2008)
  23. Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents. Alam MM, Lee SC, Jung Y, Yun HJ, Min HY, Lee HJ, Pham PC, Moon J, Kwon DI, Lim B, Suh YG, Lee J, Lee HY. Oncotarget 6 40598-40610 (2015)
  24. Comment Oxygenases get to grips with polypeptides. Bugg TD. Structure 17 913-914 (2009)
  25. Structural basis for the inhibitor recognition of human Lyn kinase domain. Miyano N, Kinoshita T, Nakai R, Kirii Y, Yokota K, Tada T. Bioorg. Med. Chem. Lett. 19 6557-6560 (2009)
  26. Theoretical studies of the role of C-terminal cysteines in the process of S-nitrosylation of human Src kinases. Andre FR, dos Santos PF, Rando DG. J Mol Model 22 23 (2016)
  27. Hsp90 dependence of a kinase is determined by its conformational landscape. Luo Q, Boczek EE, Wang Q, Buchner J, Kaila VR. Sci Rep 7 43996 (2017)