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5y8u

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Revision as of 09:13, 21 October 2020

Crystal structure of the C276S mutant of MAP2K7

Structural highlights

5y8u is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Activity:	Mitogen-activated protein kinase kinase, with EC number 2.7.12.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MP2K7_HUMAN] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by proinflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.^[1] ^[2] ^[3] [:]

Publication Abstract from PubMed

Mitogen-activated protein kinase kinase 7 (MAP2K7) regulates stress and inflammatory responses, and is an attractive drug discovery target for several diseases including arthritis and cardiac hypertrophy. Intracellular proteins such as MAP2K7 are prone to aggregation due to cysteine-driven oxidation in in vitro experiments. MAP2K7 instability due to the four free cysteine residues on the molecular surface abrogated the crystal growth and led to a low-resolution structure with large residual errors. To acquire a higher resolution structure for promoting rational drug discovery, we explored stable mutants of MAP2K7 by replacing the surface cysteine residues, Cys147, Cys218, Cys276 and Cys296. Single-site mutations, except for Cys147, maintained the specific activity and increased the protein yield, while all the multi-site mutations massively reduced the activity. The C218S mutation drastically augmented the protein production and crystallographic resolution. Furthermore, the C218S crystals grown under microgravity in a space environment yielded a 1.3 A resolution structure, providing novel insights for drug discovery: the precisely assigned water molecules in the active site, the double conformations in the flexible region and the C-terminal extension bound to the N-terminal region of the adjacent molecules. The latter insight is likely to promote the production of allosteric MAP2K7 inhibitors.

High-resolution structure discloses the potential for allosteric regulation of mitogen-activated protein kinase kinase 7.,Kinoshita T, Hashimoto T, Sogabe Y, Fukada H, Matsumoto T, Sawa M Biochem Biophys Res Commun. 2017 Sep 7. pii: S0006-291X(17)31785-0. doi:, 10.1016/j.bbrc.2017.09.025. PMID:28890347^[4]

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

References

↑ Wu Z, Wu J, Jacinto E, Karin M. Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase. Mol Cell Biol. 1997 Dec;17(12):7407-16. PMID:9372971
↑ Lu X, Nemoto S, Lin A. Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. J Biol Chem. 1997 Oct 3;272(40):24751-4. PMID:9312068
↑ Foltz IN, Gerl RE, Wieler JS, Luckach M, Salmon RA, Schrader JW. Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J Biol Chem. 1998 Apr 10;273(15):9344-51. PMID:9535930
↑ Kinoshita T, Hashimoto T, Sogabe Y, Fukada H, Matsumoto T, Sawa M. High-resolution structure discloses the potential for allosteric regulation of mitogen-activated protein kinase kinase 7. Biochem Biophys Res Commun. 2017 Sep 7. pii: S0006-291X(17)31785-0. doi:, 10.1016/j.bbrc.2017.09.025. PMID:28890347 doi:http://dx.doi.org/10.1016/j.bbrc.2017.09.025

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5y8u"

Categories: Large Structures | Mitogen-activated protein kinase kinase | Kinoshita, T | Protein kinase | Transferase

@@ Line 1: / Line 1: @@
 ==Crystal structure of the C276S mutant of MAP2K7==
-<StructureSection load='5y8u' size='340' side='right' caption='[[5y8u]], [[Resolution|resolution]] 2.92&Aring;' scene=''>
+<StructureSection load='5y8u' size='340' side='right'caption='[[5y8u]], [[Resolution|resolution]] 2.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5y8u]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y8U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y8U FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5y8u]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y8U OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5Y8U FirstGlance]. <br>
 </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 Mitogen-activated protein kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.2 2.7.12.2] </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=5y8u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y8u OCA], [http://pdbe.org/5y8u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y8u RCSB], [http://www.ebi.ac.uk/pdbsum/5y8u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y8u ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5y8u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y8u OCA], [http://pdbe.org/5y8u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y8u RCSB], [http://www.ebi.ac.uk/pdbsum/5y8u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y8u ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Mitogen-activated protein kinase kinase]]
 [[Category: Kinoshita, T]]
 [[Category: Protein kinase]]
 [[Category: Transferase]]

5y8u

From Proteopedia

Revision as of 09:13, 21 October 2020

Crystal structure of the C276S mutant of MAP2K7

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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