2ptj
From Proteopedia
(New page: 200px<br /> <applet load="2ptj" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ptj, resolution 2.200Å" /> '''Crystal Structure ...) |
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caption="2ptj, resolution 2.200Å" /> | caption="2ptj, resolution 2.200Å" /> | ||
'''Crystal Structure of F169R p38 Kinase'''<br /> | '''Crystal Structure of F169R p38 Kinase'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2PTJ 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 BOG as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] Full crystallographic information is available from [http:// | + | 2PTJ 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=BOG:'>BOG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PTJ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: protein kinase]] | [[Category: protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:56:14 2008'' |
Revision as of 12:56, 23 January 2008
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Crystal Structure of F169R p38 Kinase
Overview
In order to study the role of Phe169 in p38alpha MAP kinase structure and, function, wild-type p38alpha and five p38alpha DFG motif mutants were, examined in vitro for phosphorylation by MKK6, kinase activity toward ATF2, substrate, thermal stability, and X-ray crystal structure. All six, p38alpha variants were efficiently phosphorylated by MKK6. However, only, one activated p38alpha mutant (F169Y) possessed measurable kinase activity, (1% compared to wild-type). The loss of kinase activity among the DFG, mutants may result from an inability to correctly position Asp168 in the, activated form of p38alpha. Two mutations significantly increased the, thermal stability of p38alpha (F169A DeltaTm = 1.3 degrees C and D168G, DeltaTm = 3.8 degrees C), and two mutations significantly decreased the, stability of p38alpha (F169R DeltaTm = -3.2 degrees C and F169G DeltaTm =, -4.7 degrees C). Interestingly, X-ray crystal structures of two thermally, destabilized p38alpha-F169R and p38alpha-F169G mutants revealed a DFG-OUT, conformation in the absence of an inhibitor molecule. This DFG-OUT, conformation, termed alpha-DFG-OUT, is different from the ones previously, identified in p38alpha crystal structures with bound inhibitors and, postulated from high-temperature molecular dynamics simulations. Taken, together, these results indicate that Phe169 is optimized for p38alpha, functional activity and structural dynamics, rather than for structural, stability. The alpha-DFG-OUT conformation observed for p38alpha-F169R and, p38alpha-F169G may represent a naturally occurring intermediate state of, p38alpha that provides access for binding of allosteric inhibitors. A, model of the local forces driving the DFG IN-OUT transition in p38alpha is, proposed.
About this Structure
2PTJ is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Mitogen-activated protein kinase, with EC number 2.7.11.24 Full crystallographic information is available from OCA.
Reference
Mutagenesis of p38alpha MAP kinase establishes key roles of Phe169 in function and structural dynamics and reveals a novel DFG-OUT state., Bukhtiyarova M, Karpusas M, Northrop K, Namboodiri HV, Springman EB, Biochemistry. 2007 May 15;46(19):5687-96. Epub 2007 Apr 19. PMID:17441692
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