View source for 4an3


==Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.==
<StructureSection load='4an3' size='340' side='right' caption='[[4an3]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4an3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AN3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AN3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5Y0:N-[(2S)-2,3-BIS(OXIDANYL)PROPOXY]-3,4-BIS(FLUORANYL)-2-[(2-FLUORANYL-4-IODANYL-PHENYL)AMINO]BENZAMIDE'>5Y0</scene>, <scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1s9j|1s9j]], [[4an2|4an2]], [[4an9|4an9]], [[4anb|4anb]]</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=4an3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4an3 OCA], [http://pdbe.org/4an3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4an3 RCSB], [http://www.ebi.ac.uk/pdbsum/4an3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4an3 ProSAT]</span></td></tr>
</table>
== 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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperid in-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973).,Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L, Engst S, Joshi AA, Kennedy AR, Kim AI, Koltun ES, Lougheed JC, Manalo JC, Martini JF, Nuss JM, Peto CJ, Tsang TH, Yu P, Johnston S ACS Med Chem Lett. 2012 Apr 9;3(5):416-21. doi: 10.1021/ml300049d. eCollection, 2012 May 10. PMID:24900486<ref>PMID:24900486</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4an3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mitogen-activated protein kinase kinase|Mitogen-activated protein kinase kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mitogen-activated protein kinase kinase]]
[[Category: Aay, N]]
[[Category: Anand, N K]]
[[Category: Blazey, C M]]
[[Category: Bowles, O J]]
[[Category: Bussenius, J]]
[[Category: Costanzo, S]]
[[Category: Curtis, J K]]
[[Category: Defina, S C]]
[[Category: Dubenko, L]]
[[Category: Engst, S]]
[[Category: Johnston, S]]
[[Category: Joshi, A A]]
[[Category: Kennedy, A R]]
[[Category: Kim, A I]]
[[Category: Koltun, E S]]
[[Category: Lougheed, J C]]
[[Category: Manalo, J C.L]]
[[Category: Martini, J F]]
[[Category: Nuss, J M]]
[[Category: Peto, C J]]
[[Category: Rice, K D]]
[[Category: Tsang, T H]]
[[Category: Yu, P]]
[[Category: Allosteric inhibition]]
[[Category: Atp-binding]]
[[Category: Map2k1]]
[[Category: Transferase]]