4usd

Human STK10 (LOK) with SB-633825Human STK10 (LOK) with SB-633825

Structural highlights

4usd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.05Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

STK10_HUMAN The disease may be caused by mutations affecting the gene represented in this entry.^[1]

Function

STK10_HUMAN Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo.^[2] ^[3] ^[4]

Publication Abstract from PubMed

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

Comprehensive characterization of the Published Kinase Inhibitor Set.,Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Muller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ Nat Biotechnol. 2015 Oct 26. doi: 10.1038/nbt.3374. PMID:26501955^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bignell G, Smith R, Hunter C, Stephens P, Davies H, Greenman C, Teague J, Butler A, Edkins S, Stevens C, O'Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Gillis AJ, Stoop HJ, van Gurp RJ, Oosterhuis JW, Looijenga LH, Futreal PA, Wooster R, Stratton MR. Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer. 2006 Jan;45(1):42-6. PMID:16175573 doi:http://dx.doi.org/10.1002/gcc.20265
↑ Tao L, Wadsworth S, Mercer J, Mueller C, Lynn K, Siekierka J, August A. Opposing roles of serine/threonine kinases MEKK1 and LOK in regulating the CD28 responsive element in T-cells. Biochem J. 2002 Apr 1;363(Pt 1):175-82. PMID:11903060
↑ Walter SA, Cutler RE Jr, Martinez R, Gishizky M, Hill RJ. Stk10, a new member of the polo-like kinase kinase family highly expressed in hematopoietic tissue. J Biol Chem. 2003 May 16;278(20):18221-8. Epub 2003 Mar 13. PMID:12639966 doi:http://dx.doi.org/10.1074/jbc.M212556200
↑ Belkina NV, Liu Y, Hao JJ, Karasuyama H, Shaw S. LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4707-12. doi:, 10.1073/pnas.0805963106. Epub 2009 Mar 2. PMID:19255442 doi:http://dx.doi.org/10.1073/pnas.0805963106
↑ Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Muller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ. Comprehensive characterization of the Published Kinase Inhibitor Set. Nat Biotechnol. 2015 Oct 26. doi: 10.1038/nbt.3374. PMID:26501955 doi:http://dx.doi.org/10.1038/nbt.3374

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Bignell G, Smith R, Hunter C, Stephens P, Davies H, Greenman C, Teague J, Butler A, Edkins S, Stevens C, O'Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Gillis AJ, Stoop HJ, van Gurp RJ, Oosterhuis JW, Looijenga LH, Futreal PA, Wooster R, Stratton MR. Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer. 2006 Jan;45(1):42-6. PMID:16175573 doi:http://dx.doi.org/10.1002/gcc.20265

[2] Tao L, Wadsworth S, Mercer J, Mueller C, Lynn K, Siekierka J, August A. Opposing roles of serine/threonine kinases MEKK1 and LOK in regulating the CD28 responsive element in T-cells. Biochem J. 2002 Apr 1;363(Pt 1):175-82. PMID:11903060

[3] Walter SA, Cutler RE Jr, Martinez R, Gishizky M, Hill RJ. Stk10, a new member of the polo-like kinase kinase family highly expressed in hematopoietic tissue. J Biol Chem. 2003 May 16;278(20):18221-8. Epub 2003 Mar 13. PMID:12639966 doi:http://dx.doi.org/10.1074/jbc.M212556200

[4] Belkina NV, Liu Y, Hao JJ, Karasuyama H, Shaw S. LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4707-12. doi:, 10.1073/pnas.0805963106. Epub 2009 Mar 2. PMID:19255442 doi:http://dx.doi.org/10.1073/pnas.0805963106

[5] Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Muller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ. Comprehensive characterization of the Published Kinase Inhibitor Set. Nat Biotechnol. 2015 Oct 26. doi: 10.1038/nbt.3374. PMID:26501955 doi:http://dx.doi.org/10.1038/nbt.3374

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