2f57

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Crystal Structure Of The Human P21-Activated Kinase 5

Structural highlights

2f57 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 1.8Å
Ligands:23D, SEP, TRS
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAK5_HUMAN Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates the proto-oncogene RAF1 and stimulates its kinase activity. Promotes cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Phosphorylates CTNND1, probably to regulate cytoskeletal organization and cell morphology. Keeps microtubules stable through MARK2 inhibition and destabilizes the F-actin network leading to the disappearance of stress fibers and focal adhesions.[1] [2] [3] [4] [5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix alphaC, a key regulatory element of kinase function, resulted in an additional helical turn at the alphaC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, alphaC, and the activation segment and firmly anchor alphaC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.

Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.,Eswaran J, Lee WH, Debreczeni JE, Filippakopoulos P, Turnbull A, Fedorov O, Deacon SW, Peterson JR, Knapp S Structure. 2007 Feb;15(2):201-13. PMID:17292838[6]

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

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Citations
21 reviews cite this structure
A tale of two Paks.
Arias-Romero et al. (2008)
20 more
45 other articles
No citations found

See Also

References

  1. ↑ Cotteret S, Jaffer ZM, Beeser A, Chernoff J. p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol. 2003 Aug;23(16):5526-39. PMID:12897128
  2. ↑ Matenia D, Griesshaber B, Li XY, Thiessen A, Johne C, Jiao J, Mandelkow E, Mandelkow EM. PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin. Mol Biol Cell. 2005 Sep;16(9):4410-22. Epub 2005 Jul 12. PMID:16014608 doi:http://dx.doi.org/10.1091/mbc.E05-01-0081
  3. ↑ Cotteret S, Chernoff J. Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties. Mol Cell Biol. 2006 Apr;26(8):3215-30. PMID:16581795 doi:http://dx.doi.org/10.1128/MCB.26.8.3215-3230.2006
  4. ↑ Wu X, Carr HS, Dan I, Ruvolo PP, Frost JA. p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J Cell Biochem. 2008 Sep 1;105(1):167-75. doi: 10.1002/jcb.21809. PMID:18465753 doi:http://dx.doi.org/10.1002/jcb.21809
  5. ↑ Wong LE, Reynolds AB, Dissanayaka NT, Minden A. p120-catenin is a binding partner and substrate for Group B Pak kinases. J Cell Biochem. 2010 Aug 1;110(5):1244-54. doi: 10.1002/jcb.22639. PMID:20564219 doi:http://dx.doi.org/10.1002/jcb.22639
  6. ↑ Eswaran J, Lee WH, Debreczeni JE, Filippakopoulos P, Turnbull A, Fedorov O, Deacon SW, Peterson JR, Knapp S. Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs. Structure. 2007 Feb;15(2):201-13. PMID:17292838 doi:10.1016/j.str.2007.01.001

Contents


PDB ID 2f57

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