2ou7: Difference between revisions
New page: left|200px<br /> <applet load="2ou7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ou7, resolution 2.40Å" /> '''Structure of the Ca... |
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'''Structure of the Catalytic Domain of Human Polo-like Kinase 1'''<br /> | '''Structure of the Catalytic Domain of Human Polo-like Kinase 1'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
2OU7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, ACT, MG and ANP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] Full crystallographic information is available from [http:// | 2OU7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=ANP:'>ANP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OU7 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: kinase domain]] | [[Category: kinase domain]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:56:51 2008'' | ||
Revision as of 14:56, 23 January 2008
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Structure of the Catalytic Domain of Human Polo-like Kinase 1
OverviewOverview
Polo-like kinase 1 (Plk1) is an attractive target for the development of, anticancer agents due to its importance in regulating cell-cycle, progression. Overexpression of Plk1 has been detected in a variety of, cancers, and expression levels often correlate with poor prognosis., Despite high interest in Plk1-targeted therapeutics, there is currently no, structure publicly available to guide structure-based drug design of, specific inhibitors. We determined the crystal structures of the T210V, mutant of the kinase domain of human Plk1 complexed with the, nonhydrolyzable ATP analogue adenylylimidodiphosphate (AMPPNP) or the, pyrrolo-pyrazole inhibitor PHA-680626 at 2.4 and 2.1 A resolution, respectively. Plk1 adopts the typical kinase domain fold and crystallized, in a conformation resembling the active state of other kinases. Comparison, of the kinetic parameters determined for the (unphosphorylated) wild-type, enzyme, as well as the T210V and T210D mutants, shows that the mutations, primarily affect the kcat of the reaction, with little change in the, apparent Km for the protein or nucleotide substrates (kcat = 0.0094, 0.0376, and 0.0049 s-1 and Km(ATP) = 3.2, 4.0, and 3.0 microM for WT, T210D, and T210V, respectively). The structure highlights features of the, active site that can be exploited to obtain Plk1-specific inhibitors with, selectivity over other kinases and Plk isoforms. These include the, presence of a phenylalanine at the bottom of the ATP pocket, combined with, a cysteine (as opposed to the more commonly found leucine) in the roof of, the binding site, a pocket created by Leu132 in the hinge region, and a, cluster of positively charged residues in the solvent-exposed area outside, of the adenine pocket adjacent to the hinge region.
About this StructureAbout this Structure
2OU7 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Polo kinase, with EC number 2.7.11.21 Full crystallographic information is available from OCA.
ReferenceReference
Structure of the catalytic domain of human polo-like kinase 1., Kothe M, Kohls D, Low S, Coli R, Cheng AC, Jacques SL, Johnson TL, Lewis C, Loh C, Nonomiya J, Sheils AL, Verdries KA, Wynn TA, Kuhn C, Ding YH, Biochemistry. 2007 May 22;46(20):5960-71. Epub 2007 Apr 27. PMID:17461553
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