4b95

pVHL-EloB-EloB-EloC complex_(2S,4R)-1-(2-chlorophenyl)carbonyl-N-[(4-chlorophenyl)methyl]-4-oxidanyl-pyrrolidine-2-carboxamide bound

spinqualitylabelsall models 4b95, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4b95 is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, UCK Related: 1lm8, 1lqb, 1vcb, 2c9w, 2izv, 2xai, 3zrc, 3zrf, 3ztc, 3ztd, 3zun, 4ajy, 4awj, 4b9k Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [VHL_HUMAN] Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:171300]. A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years. [:] Defects in VHL are the cause of familial erythrocytosis type 2 (ECYT2) [MIM:263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events. Defects in VHL are a cause of renal cell carcinoma (RCC) [MIM:144700]. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Function [ELOB_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex). The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes. [VHL_HUMAN] Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2. [ELOC_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex). The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes. Publication Abstract from PubMed By design: Novel small-molecule inhibitors of the interaction between the von Hippel-Lindau ligase (VHL) and its molecular target HIF1alpha, a transcription factor involved in oxygen sensing, have been developed and studied. The most potent inhibitor binds with an IC(50) value of 0.9 microM and is thus the first sub-micromolar inhibitor of the VHL-HIF1alpha interaction. Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1alpha,Buckley DL, Gustafson JL, Van Molle I, Roth AG, Tae HS, Gareiss PC, Jorgensen WL, Ciulli A, Crews CM Angew Chem Int Ed Engl. 2012 Oct 12. doi: 10.1002/anie.201206231. PMID:23065727 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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