4mbj | pdb_00004mbj

Human B-Raf Kinase Domain in Complex with an Imidazopyridine-based Inhibitor

spinqualitylabelsall models 4mbj, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mbj is a 2 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: DFS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRAF_HUMAN Note=Defects in BRAF are found in a wide range of cancers. Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:114500. Defects in BRAF are involved in lung cancer (LNCR) [MIM:211980. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:605027. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. Defects in BRAF 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. Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:613706. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits. Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:613707. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. Function BRAF_HUMAN Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Publication Abstract from PubMed This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, alphaC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity. Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase.,Newhouse BJ, Wenglowsky S, Grina J, Laird ER, Voegtli WC, Ren L, Ahrendt K, Buckmelter A, Gloor SL, Klopfenstein N, Rudolph J, Wen Z, Li X, Feng B Bioorg Med Chem Lett. 2013 Aug 29. pii: S0960-894X(13)01026-3. doi:, 10.1016/j.bmcl.2013.08.086. PMID:24042006 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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