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{{STRUCTURE_4bie| PDB=4bie | SCENE= }}  
==Crystal Structures of Ask1-inhibitor Complexes==
===Crystal Structures of Ask1-inhibitor Complexes===
<StructureSection load='4bie' size='340' side='right' caption='[[4bie]], [[Resolution|resolution]] 2.36&Aring;' scene=''>
{{ABSTRACT_PUBMED_23776076}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4bie]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BIE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BIE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IE6:N-(2-AMINOETHYL)-5-{2-METHYL-1H-PYRROLO[2,3-B]PYRIDIN-4-YL}THIOPHENE-2-SULFONAMIDE'>IE6</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bf2|4bf2]], [[4bhn|4bhn]], [[4bib|4bib]], [[4bic|4bic]], [[4bid|4bid]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bie OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bie RCSB], [http://www.ebi.ac.uk/pdbsum/4bie PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.


==Function==
Crystal structures of ASK1-inhibtor complexes provide a platform for structure based drug design.,Singh O, Shillings A, Craggs P, Wall I, Rowland P, Skarzynski T, Hobbs CI, Hardwick P, Tanner R, Blunt M, Witty DR, Smith KJ Protein Sci. 2013 Jun 15. doi: 10.1002/pro.2298. PMID:23776076<ref>PMID:23776076</ref>
[[http://www.uniprot.org/uniprot/M3K5_HUMAN M3K5_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).<ref>PMID:8940179</ref> <ref>PMID:8974401</ref> <ref>PMID:9564042</ref> <ref>PMID:9774977</ref> <ref>PMID:10411906</ref> <ref>PMID:10849426</ref> <ref>PMID:10688666</ref> <ref>PMID:11689443</ref> <ref>PMID:11029458</ref> <ref>PMID:11154276</ref> <ref>PMID:14749717</ref> <ref>PMID:11920685</ref> <ref>PMID:12697749</ref> <ref>PMID:15023544</ref> <ref>PMID:14688258</ref> <ref>PMID:16129676</ref> <ref>PMID:17220297</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4bie]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BIE OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:023776076</ref><references group="xtra"/><references/>
*[[Mitogen-activated protein kinase kinase kinase|Mitogen-activated protein kinase kinase kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Mitogen-activated protein kinase kinase kinase]]
[[Category: Blunt, M.]]
[[Category: Blunt, M]]
[[Category: Craggs, P.]]
[[Category: Craggs, P]]
[[Category: Hardwick, P.]]
[[Category: Hardwick, P]]
[[Category: Hobbs, C I.]]
[[Category: Hobbs, C I]]
[[Category: Rowland, P.]]
[[Category: Rowland, P]]
[[Category: Shillings, A.]]
[[Category: Shillings, A]]
[[Category: Singh, O.]]
[[Category: Singh, O]]
[[Category: Skarzynski, T.]]
[[Category: Skarzynski, T]]
[[Category: Smith, K J.]]
[[Category: Smith, K J]]
[[Category: Tanner, R.]]
[[Category: Tanner, R]]
[[Category: Wall, I.]]
[[Category: Wall, I]]
[[Category: Witty, D R.]]
[[Category: Witty, D R]]
[[Category: Structure based desgin]]
[[Category: Structure based desgin]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 12:54, 21 December 2014

Crystal Structures of Ask1-inhibitor ComplexesCrystal Structures of Ask1-inhibitor Complexes

Structural highlights

4bie 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.
Ligands:,
Activity:Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

Crystal structures of ASK1-inhibtor complexes provide a platform for structure based drug design.,Singh O, Shillings A, Craggs P, Wall I, Rowland P, Skarzynski T, Hobbs CI, Hardwick P, Tanner R, Blunt M, Witty DR, Smith KJ Protein Sci. 2013 Jun 15. doi: 10.1002/pro.2298. PMID:23776076[1]

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

See Also

References

  1. ↑ Singh O, Shillings A, Craggs P, Wall I, Rowland P, Skarzynski T, Hobbs CI, Hardwick P, Tanner R, Blunt M, Witty DR, Smith KJ. Crystal structures of ASK1-inhibtor complexes provide a platform for structure based drug design. Protein Sci. 2013 Jun 15. doi: 10.1002/pro.2298. PMID:23776076 doi:10.1002/pro.2298

4bie, resolution 2.36Å

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