1unq

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1unq, resolution 0.98Å ()
Ligands:
Non-Standard Residues:
Related: 1h10, 1unp, 1unr
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


HIGH RESOLUTION CRYSTAL STRUCTURE OF THE PLECKSTRIN HOMOLOGY DOMAIN OF PROTEIN KINASE B/AKT BOUND TO INS (1,3,4,5)-TETRAKISPHOPHATE

Publication Abstract from PubMed

Protein kinase B (PKB/Akt) is a key regulator of cell growth, proliferation and metabolism. It possesses an N-terminal pleckstrin homology (PH) domain that interacts with equal affinity with the second messengers PtdIns(3,4,5)P3 and PtdIns(3,4)P2, generated through insulin and growth factor-mediated activation of phosphoinositide 3-kinase (PI3K). The binding of PKB to PtdIns(3,4,5)P3/PtdIns(3,4)P2 recruits PKB from the cytosol to the plasma membrane and is also thought to induce a conformational change that converts PKB into a substrate that can be activated by the phosphoinositide-dependent kinase 1 (PDK1). In this study we describe two high-resolution crystal structures of the PH domain of PKBalpha in a noncomplexed form and compare this to a new atomic resolution (0.98 A, where 1 A=0.1 nm) structure of the PH domain of PKBalpha complexed to Ins(1,3,4,5)P4, the head group of PtdIns(3,4,5)P3. Remarkably, in contrast to all other PH domains crystallized so far, our data suggest that binding of Ins(1,3,4,5)P4 to the PH domain of PKB, induces a large conformational change. This is characterized by marked changes in certain residues making up the phosphoinositide-binding site, formation of a short a-helix in variable loop 2, and a movement of variable loop 3 away from the lipid-binding site. Solution studies with CD also provided evidence of conformational changes taking place upon binding of Ins(1,3,4,5)P4 to the PH domain of PKB. Our data provides the first structural insight into the mechanism by which the interaction of PKB with PtdIns(3,4,5)P3/PtdIns(3,4)P2 induces conformational changes that could enable PKB to be activated by PDK1.

Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change., Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM, Biochem J. 2003 Nov 1;375(Pt 3):531-8. PMID:12964941

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

About this Structure

1unq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem J. 2003 Nov 1;375(Pt 3):531-8. PMID:12964941 doi:http://dx.doi.org/10.1042/BJ20031229
  • Thomas CC, Deak M, Alessi DR, van Aalten DM. High-resolution structure of the pleckstrin homology domain of protein kinase b/akt bound to phosphatidylinositol (3,4,5)-trisphosphate. Curr Biol. 2002 Jul 23;12(14):1256-62. PMID:12176338
  • Chen X, Weber I, Harrison RW. Hydration water and bulk water in proteins have distinct properties in radial distributions calculated from 105 atomic resolution crystal structures. J Phys Chem B. 2008 Sep 25;112(38):12073-80. Epub 2008 Aug 28. PMID:18754631 doi:10.1021/jp802795a

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