4eqc

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Crystal structure of PAK1 kinase domain in complex with FRAX597 inhibitor

Structural highlights

4eqc is a 1 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 2.01Å
Ligands:CL, TPO, XR1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAK1_HUMAN Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

Publication Abstract from PubMed

The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.

FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas.,Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL J Biol Chem. 2013 Oct 4;288(40):29105-29114. Epub 2013 Aug 19. PMID:23960073[16]

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

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See Also

References

  1. ↑ Brown JL, Stowers L, Baer M, Trejo J, Coughlin S, Chant J. Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr Biol. 1996 May 1;6(5):598-605. PMID:8805275
  2. ↑ Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol. 1997 Mar 1;7(3):202-10. PMID:9395435
  3. ↑ Manser E, Huang HY, Loo TH, Chen XQ, Dong JM, Leung T, Lim L. Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes. Mol Cell Biol. 1997 Mar;17(3):1129-43. PMID:9032240
  4. ↑ Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol. 1998 Apr;18(4):2153-63. PMID:9528787
  5. ↑ Zenke FT, King CC, Bohl BP, Bokoch GM. Identification of a central phosphorylation site in p21-activated kinase regulating autoinhibition and kinase activity. J Biol Chem. 1999 Nov 12;274(46):32565-73. PMID:10551809
  6. ↑ Zang M, Hayne C, Luo Z. Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. J Biol Chem. 2002 Feb 8;277(6):4395-405. Epub 2001 Nov 30. PMID:11733498 doi:10.1074/jbc.M110000200
  7. ↑ Chen S, Yin X, Zhu X, Yan J, Ji S, Chen C, Cai M, Zhang S, Zong H, Hu Y, Yuan Z, Shen Z, Gu J. The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis. J Biol Chem. 2003 May 30;278(22):20029-36. Epub 2003 Mar 6. PMID:12624090 doi:10.1074/jbc.M300818200
  8. ↑ Slack-Davis JK, Eblen ST, Zecevic M, Boerner SA, Tarcsafalvi A, Diaz HB, Marshall MS, Weber MJ, Parsons JT, Catling AD. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol. 2003 Jul 21;162(2):281-91. PMID:12876277 doi:10.1083/jcb.200212141
  9. ↑ Zhou GL, Zhuo Y, King CC, Fryer BH, Bokoch GM, Field J. Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol. 2003 Nov;23(22):8058-69. PMID:14585966
  10. ↑ Zhou H, Kramer RH. Integrin engagement differentially modulates epithelial cell motility by RhoA/ROCK and PAK1. J Biol Chem. 2005 Mar 18;280(11):10624-35. Epub 2004 Dec 17. PMID:15611088 doi:10.1074/jbc.M411900200
  11. ↑ Vadlamudi RK, Barnes CJ, Rayala S, Li F, Balasenthil S, Marcus S, Goodson HV, Sahin AA, Kumar R. p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol Cell Biol. 2005 May;25(9):3726-36. PMID:15831477 doi:25/9/3726
  12. ↑ Talukder AH, Meng Q, Kumar R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene. 2006 Mar 2;25(9):1311-9. PMID:16278681 doi:1209172
  13. ↑ Rider L, Shatrova A, Feener EP, Webb L, Diakonova M. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem. 2007 Oct 19;282(42):30985-96. Epub 2007 Aug 28. PMID:17726028 doi:10.1074/jbc.M701794200
  14. ↑ Mayhew MW, Jeffery ED, Sherman NE, Nelson K, Polefrone JM, Pratt SJ, Shabanowitz J, Parsons JT, Fox JW, Hunt DF, Horwitz AF. Identification of phosphorylation sites in betaPIX and PAK1. J Cell Sci. 2007 Nov 15;120(Pt 22):3911-8. PMID:17989089 doi:10.1242/jcs.008177
  15. ↑ Nie J, Sun C, Faruque O, Ye G, Li J, Liang Q, Chang Z, Yang W, Han X, Shi Y. Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-Cells. J Biol Chem. 2012 Jul 27;287(31):26435-44. doi: 10.1074/jbc.M112.378372. Epub, 2012 Jun 5. PMID:22669945 doi:10.1074/jbc.M112.378372
  16. ↑ Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL. FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013 Oct 4;288(40):29105-29114. Epub 2013 Aug 19. PMID:23960073 doi:http://dx.doi.org/10.1074/jbc.M113.510933

Contents


PDB ID 4eqc

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