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|3mbl, resolution 2.60Å ()|
|Gene:||MAP2K1, MEK 1, MEK1, PRKMK1 (Homo sapiens)|
Crystal Structure of the human mitogen-activated protein kinase kinase 1 (MEK 1) in complex with ligand and MgADP
A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties.
Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors., Wallace MB, Adams ME, Kanouni T, Mol CD, Dougan DR, Feher VA, O'Connell SM, Shi L, Halkowycz P, Dong Q, Bioorg Med Chem Lett. 2010 Jul 15;20(14):4156-8. Epub 2010 May 20. PMID:20621728
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[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.
[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.
About this Structure
- Wallace MB, Adams ME, Kanouni T, Mol CD, Dougan DR, Feher VA, O'Connell SM, Shi L, Halkowycz P, Dong Q. Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors. Bioorg Med Chem Lett. 2010 Jul 15;20(14):4156-8. Epub 2010 May 20. PMID:20621728 doi:10.1016/j.bmcl.2010.05.058
- ↑ 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