4awj

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{{STRUCTURE_4awj| PDB=4awj | SCENE= }}
 
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===pVHL:EloB:EloC complex, in complex with capped Hydroxyproline===
 
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{{ABSTRACT_PUBMED_23102223}}
 
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==Disease==
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==pVHL:EloB:EloC complex, in complex with capped Hydroxyproline==
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[[http://www.uniprot.org/uniprot/VHL_HUMAN VHL_HUMAN]] Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:[http://omim.org/entry/171300 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:[http://omim.org/entry/193300 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.<ref>PMID:10635329</ref><ref>PMID:8493574</ref><ref>PMID:7987306</ref><ref>PMID:7728151</ref><ref>PMID:8634692</ref><ref>PMID:8592333</ref><ref>PMID:8825918</ref><ref>PMID:8730290</ref><ref>PMID:8956040</ref><ref>PMID:9452032</ref><ref>PMID:9452106</ref><ref>PMID:10627136</ref><ref>PMID:9829911</ref><ref>PMID:9829912</ref>[:]<ref>PMID:10533030</ref><ref>PMID:10408776</ref><ref>PMID:16502427</ref> Defects in VHL are the cause of familial erythrocytosis type 2 (ECYT2) [MIM:[http://omim.org/entry/263400 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.<ref>PMID:12844285</ref><ref>PMID:12393546</ref> Defects in VHL are a cause of renal cell carcinoma (RCC) [MIM:[http://omim.org/entry/144700 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.<ref>PMID:11986208</ref>
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<StructureSection load='4awj' size='340' side='right'caption='[[4awj]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4awj]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AWJ FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=V6F:(4R)-1-ACETYL-4-HYDROXY-N-METHYL-L-PROLINAMIDE'>V6F</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4awj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4awj OCA], [https://pdbe.org/4awj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4awj RCSB], [https://www.ebi.ac.uk/pdbsum/4awj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4awj ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ELOB_HUMAN 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).<ref>PMID:7638163</ref> <ref>PMID:15590694</ref> 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.<ref>PMID:7638163</ref> <ref>PMID:15590694</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1alpha interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed.
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==Function==
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Dissecting fragment-based lead discovery at the von hippel-lindau protein:hypoxia inducible factor 1alpha protein-protein interface.,Van Molle I, Thomann A, Buckley DL, So EC, Lang S, Crews CM, Ciulli A Chem Biol. 2012 Oct 26;19(10):1300-12. doi: 10.1016/j.chembiol.2012.08.015. PMID:23102223<ref>PMID:23102223</ref>
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[[http://www.uniprot.org/uniprot/ELOB_HUMAN 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).<ref>PMID:7638163</ref><ref>PMID:15590694</ref> 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.<ref>PMID:7638163</ref><ref>PMID:15590694</ref> [[http://www.uniprot.org/uniprot/VHL_HUMAN 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.<ref>PMID:9751722</ref><ref>PMID:10944113</ref><ref>PMID:19584355</ref> [[http://www.uniprot.org/uniprot/ELOC_HUMAN 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).<ref>PMID:15590694</ref> 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.<ref>PMID:15590694</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4awj]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AWJ OCA].
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</div>
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<div class="pdbe-citations 4awj" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<references group="xtra"/><references/>
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*[[Elongation factor 3D structures|Elongation factor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Buckley, D L.]]
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[[Category: Large Structures]]
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[[Category: Ciulli, A.]]
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[[Category: Buckley DL]]
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[[Category: Crews, C M.]]
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[[Category: Ciulli A]]
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[[Category: Lang, S.]]
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[[Category: Crews CM]]
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[[Category: Molle, I Van.]]
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[[Category: Lang S]]
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[[Category: So, E C.]]
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[[Category: So EC]]
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[[Category: Thomann, A.]]
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[[Category: Thomann A]]
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[[Category: E3 ubiquitin ligase]]
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[[Category: Van Molle I]]
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[[Category: Transcription]]
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[[Category: Tumor supressor]]
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Current revision

pVHL:EloB:EloC complex, in complex with capped Hydroxyproline

PDB ID 4awj

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