3vn9

From Proteopedia

(Difference between revisions)

Current revision

Rifined Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state

Structural highlights

3vn9 is a 1 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 3an0. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MP2K6_HUMAN Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 A resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short alpha-helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the alphaC-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the gamma-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices.

Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state.,Matsumoto T, Kinoshita T, Matsuzaka H, Nakai R, Kirii Y, Yokota K, Tada T J Biochem. 2012 May;151(5):541-9. Epub 2012 Mar 1. PMID:22383536^[9]

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

References

↑ Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247-55. PMID:8622669
↑ Stein B, Brady H, Yang MX, Young DB, Barbosa MS. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996 May 10;271(19):11427-33. PMID:8626699
↑ Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074
↑ Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563-71. PMID:9218798 doi:http://dx.doi.org/10.1093/emboj/16.12.3563
↑ Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000 Sep 1;96(5):1844-52. PMID:10961885
↑ Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Haussinger D. The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Biol Chem. 2001 Oct;382(10):1447-53. PMID:11727828 doi:http://dx.doi.org/10.1515/BC.2001.178
↑ Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk SP, Schneider MC, Lu ML. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005 Feb 4;280(5):3323-30. Epub 2004 Nov 18. PMID:15550393 doi:http://dx.doi.org/10.1074/jbc.M406701200
↑ Kim MY, Choi TY, Kim JH, Lee JH, Kim JG, Sohn KC, Yoon KS, Kim CD, Lee JH, Yoon TJ. MKK6 increases the melanocyte dendricity through the regulation of Rho family GTPases. J Dermatol Sci. 2010 Nov;60(2):114-9. doi: 10.1016/j.jdermsci.2010.08.006. Epub, 2010 Sep 24. PMID:20869211 doi:http://dx.doi.org/10.1016/j.jdermsci.2010.08.006
↑ Matsumoto T, Kinoshita T, Matsuzaka H, Nakai R, Kirii Y, Yokota K, Tada T. Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state. J Biochem. 2012 May;151(5):541-9. Epub 2012 Mar 1. PMID:22383536 doi:10.1093/jb/mvs023

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3vn9"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 3vn9 is ON HOLD
+==Rifined Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state==
+<StructureSection load='3vn9' size='340' side='right'caption='[[3vn9]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3vn9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3an0 3an0]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VN9 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANK:9-{5-O-[(R)-HYDROXY{[(S)-HYDROXY(PHOSPHONOAMINO)PHOSPHORYL]OXY}PHOSPHORYL]-BETA-L-RIBOFURANOSYL}-9H-PURIN-6-AMINE'>ANK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vn9 OCA], [https://pdbe.org/3vn9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vn9 RCSB], [https://www.ebi.ac.uk/pdbsum/3vn9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vn9 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/MP2K6_HUMAN MP2K6_HUMAN] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.<ref>PMID:8622669</ref> <ref>PMID:8626699</ref> <ref>PMID:8663074</ref> <ref>PMID:9218798</ref> <ref>PMID:10961885</ref> <ref>PMID:11727828</ref> <ref>PMID:15550393</ref> <ref>PMID:20869211</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 A resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short alpha-helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the alphaC-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the gamma-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices.
-Authors: Takayoshi Kinoshita, Hitomi Matsuzaka, Ryoko Nakai, Yasuyuki Kirii, Koichi Yokota, Toshiji Tada, Takashi Matsumoto
+Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state.,Matsumoto T, Kinoshita T, Matsuzaka H, Nakai R, Kirii Y, Yokota K, Tada T J Biochem. 2012 May;151(5):541-9. Epub 2012 Mar 1. PMID:22383536<ref>PMID:22383536</ref>
-Description: Rifined Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3vn9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Mitogen-activated protein kinase kinase 3D structures|Mitogen-activated protein kinase kinase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kinoshita T]]
+[[Category: Kirii Y]]
+[[Category: Matsumoto T]]
+[[Category: Matsuzaka H]]
+[[Category: Nakai R]]
+[[Category: Tada T]]
+[[Category: Yokota K]]

3vn9

From Proteopedia

Current revision

Rifined Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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