3eqc

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a ternary complex with compound 1, ATP-GS AND MG2PX-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a ternary complex with compound 1, ATP-GS AND MG2P

Structural highlights 3eqc 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. Ligands: , , , , Related: 3eqd, 3eqf, 3eqg, 3eqh, 3eqi Gene: MAP2K1, MEK1, PRKMK1 (Homo sapiens) Activity: Mitogen-activated protein kinase kinase, with EC number 2.7.12.2 Resources: FirstGlance, OCA, RCSB, PDBsum 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed MEK1 is a member of the MAPK signal transduction pathway that responds to growth factors and cytokines. We have determined that the kinase domain spans residue 35 to 382 by proteolytic cleavage. The complete kinase domain has been crystallized and its X-ray crystal structure as a complex with magnesium and ATP-S determined at 2.1 ?. Unlike crystals of a truncated kinase domain previously published, the crystals of the intact domain can be grown either as a binary complex with a nucleotide or a ternary complex with a nucleotide and one of a multitude of allosteric inhibitors. Further the crystals allow for the determination of co-structures with ATP competitive inhibitors. We describe the structures of non-phosphorylated MEK1 (npMEK1) binary complexes with ADP, and K252a, an ATP-competitive inhibitor (see table 1) at 1.9 ?, and 2.7 ? resolution, respectively. Ternary complexes have also been solved between npMEK1, a nucleotide and an allosteric non-ATP competitive inhibitor: ATP-S with compound 1, and ADP with either U0126 or the MEK1 clinical candidate PD325089, at 1.8 ?, 2.0 ?, and 2.5 ?, respectively. Compound 1 is structurally similar to PD325901. These structures illustrate fundamental differences among various mechanisms of inhibition at the molecular level. Residues 44 to 51 have previously been shown to play a negative regulatory role in MEK1 activity. The crystal structure of the integral kinase domain provides a structural rationale for the role of these residues. They form Helix A and repress enzymatic activity by stabilizing an inactive conformation in which Helix C is displaced from its active state position. Finally, the structure provides for the first time a molecular rationale that explains how mutations in MEK may lead to the cardio-facio-cutaneous syndrome.. Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors.,Fischmann T, Smith C, Mayhood T, Myers J, Reichert P, Mannarino A, Carr D, Zhu H, Wong J, Yang RS, Le H, Madison V Biochemistry. 2009 Jan 22. PMID:19161339 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Mitogen-activated protein kinase kinase

spinqualitylabelsall models 3eqc, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image