3sls
From Proteopedia
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{{STRUCTURE_3sls| PDB=3sls | SCENE= }} | {{STRUCTURE_3sls| PDB=3sls | SCENE= }} | ||
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===Crystal Structure of human MEK-1 kinase in complex with UCB1353770 and AMPPNP=== | ===Crystal Structure of human MEK-1 kinase in complex with UCB1353770 and AMPPNP=== | ||
| + | {{ABSTRACT_PUBMED_22245778}} | ||
| + | ==Disease== | ||
| + | [[http://www.uniprot.org/uniprot/MP2K1_HUMAN MP2K1_HUMAN]] Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[http://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== | |
| - | + | [[http://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> | |
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==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
| - | <ref group="xtra">PMID:022245778</ref><ref group="xtra">PMID:022119475</ref><references group="xtra"/> | + | <ref group="xtra">PMID:022245778</ref><ref group="xtra">PMID:022119475</ref><references group="xtra"/><references/> |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase kinase]] | [[Category: Mitogen-activated protein kinase kinase]] | ||
Revision as of 00:25, 25 March 2013
Contents |
Crystal Structure of human MEK-1 kinase in complex with UCB1353770 and AMPPNP
Template:ABSTRACT PUBMED 22245778
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]
About this Structure
3sls is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Meier C, Brookings DC, Ceska TA, Doyle C, Gong H, McMillan D, Saville GP, Mushtaq A, Knight D, Reich S, Pearl LH, Powell KA, Savva R, Allen RA. Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting. J Struct Biol. 2012 Feb;177(2):329-34. Epub 2012 Jan 8. PMID:22245778 doi:10.1016/j.jsb.2012.01.002
- Laing VE, Brookings DC, Carbery RJ, Simorte JG, Hutchings MC, Langham BJ, Lowe MA, Allen RA, Fetterman JR, Turner J, Meier C, Kennedy J, Merriman M. Fused thiophene derivatives as MEK inhibitors. Bioorg Med Chem Lett. 2012 Jan 1;22(1):472-5. Epub 2011 Nov 6. PMID:22119475 doi:10.1016/j.bmcl.2011.10.105
- ↑ 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
- ↑ 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
