6zhc
From Proteopedia
(Difference between revisions)
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| - | ==== | + | ==PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL== |
| - | <StructureSection load='6zhc' size='340' side='right'caption='[[6zhc]]' scene=''> | + | <StructureSection load='6zhc' size='340' side='right'caption='[[6zhc]], [[Resolution|resolution]] 1.92Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6zhc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZHC FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=QL8:2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[2-[2-[2-[3-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-3-oxidanylidene-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-ynyl]phenoxy]propyl]-1,3-thiazole-4-carboxylic+acid'>QL8</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VHL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ELOB, TCEB2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ELOC, TCEB1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), BCL2L1, BCL2L, BCLX ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zhc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zhc OCA], [https://pdbe.org/6zhc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zhc RCSB], [https://www.ebi.ac.uk/pdbsum/6zhc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zhc ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/VHL_HUMAN VHL_HUMAN]] Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:[https://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:[https://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:[https://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:[https://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> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN]] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> [[https://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> [[https://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> [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 A heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces. | ||
| + | |||
| + | Structural Insights into PROTAC-Mediated Degradation of Bcl-xL.,Chung CW, Dai H, Fernandez E, Tinworth CP, Churcher I, Cryan J, Denyer J, Harling JD, Konopacka A, Queisser MA, Tame CJ, Watt G, Jiang F, Qian D, Benowitz AB ACS Chem Biol. 2020 Sep 18;15(9):2316-2323. doi: 10.1021/acschembio.0c00266. Epub, 2020 Aug 13. PMID:32697072<ref>PMID:32697072</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6zhc" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Chung, C]] |
| + | [[Category: Bcl-xl]] | ||
| + | [[Category: Bifunctional ligand]] | ||
| + | [[Category: E3 ligase]] | ||
| + | [[Category: Protac]] | ||
| + | [[Category: Targeted degradation]] | ||
| + | [[Category: Transcription]] | ||
| + | [[Category: Ubiquitin ligase]] | ||
Revision as of 07:21, 1 March 2021
PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL
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