4an2: Difference between revisions

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[[Image:4an2.jpg|left|200px]]


{{STRUCTURE_4an2| PDB=4an2 | SCENE= }}
==Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.==
<StructureSection load='4an2' size='340' side='right'caption='[[4an2]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4an2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AN2 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=EUI:[3,4-BIS(FLUORANYL)-2-[(2-FLUORANYL-4-IODANYL-PHENYL)AMINO]PHENYL]-[3-OXIDANYL-3-[(2S)-PIPERIDIN-2-YL]AZETIDIN-1-YL]METHANONE'>EUI</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=4an2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4an2 OCA], [https://pdbe.org/4an2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4an2 RCSB], [https://www.ebi.ac.uk/pdbsum/4an2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4an2 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MP2K1_HUMAN MP2K1_HUMAN] Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[https://omim.org/entry/115150 115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.
== Function ==
[https://www.uniprot.org/uniprot/MP2K1_HUMAN MP2K1_HUMAN] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.<ref>PMID:14737111</ref> <ref>PMID:17101779</ref>


===Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.===
==See Also==
 
*[[Mitogen-activated protein kinase kinase 3D structures|Mitogen-activated protein kinase kinase 3D structures]]
 
== References ==
==About this Structure==
<references/>
[[4an2]] is a 1 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=4AN2 OCA].
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase kinase]]
[[Category: Large Structures]]
[[Category: Aay, N.]]
[[Category: Aay N]]
[[Category: Anand, N K.]]
[[Category: Anand NK]]
[[Category: Blazey, C M.]]
[[Category: Blazey CM]]
[[Category: Bowles, O J.]]
[[Category: Bowles OJ]]
[[Category: Bussenius, J.]]
[[Category: Bussenius J]]
[[Category: Costanzo, S.]]
[[Category: Costanzo S]]
[[Category: Curtis, J K.]]
[[Category: Curtis JK]]
[[Category: Defina, S C.]]
[[Category: Defina SC]]
[[Category: Dubenko, L.]]
[[Category: Dubenko L]]
[[Category: Engst, S.]]
[[Category: Engst S]]
[[Category: Johnston, S.]]
[[Category: Johnston S]]
[[Category: Joshi, A A.]]
[[Category: Joshi AA]]
[[Category: Kennedy, A R.]]
[[Category: Kennedy AR]]
[[Category: Kim, A I.]]
[[Category: Kim AI]]
[[Category: Koltun, E S.]]
[[Category: Koltun ES]]
[[Category: Lougheed, J C.]]
[[Category: Lougheed JC]]
[[Category: Manalo, J C.L.]]
[[Category: Manalo JCL]]
[[Category: Martini, J F.]]
[[Category: Martini JF]]
[[Category: Nuss, J M.]]
[[Category: Nuss JM]]
[[Category: Peto, C J.]]
[[Category: Peto CJ]]
[[Category: Rice, K D.]]
[[Category: Rice KD]]
[[Category: Tsang, T H.]]
[[Category: Tsang TH]]
[[Category: Yu, P.]]
[[Category: Yu P]]
[[Category: Allosteric inhibition]]
[[Category: Atp-binding]]
[[Category: Map2k1]]
[[Category: Transferase]]

Latest revision as of 10:15, 1 May 2024

Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.

Structural highlights

4an2 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MP2K1_HUMAN Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.

Function

MP2K1_HUMAN Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.[1] [2]

See Also

References

  1. ↑ Liu X, Yan S, Zhou T, Terada Y, Erikson RL. The MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene. 2004 Jan 22;23(3):763-76. PMID:14737111 doi:10.1038/sj.onc.1207188
  2. ↑ Burgermeister E, Chuderland D, Hanoch T, Meyer M, Liscovitch M, Seger R. Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma. Mol Cell Biol. 2007 Feb;27(3):803-17. Epub 2006 Nov 13. PMID:17101779 doi:10.1128/MCB.00601-06

4an2, resolution 2.50Å

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