9q22
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of ternary complex Helios-ZF2:I-19:CRBN:DDB1== | |
| + | <StructureSection load='9q22' size='340' side='right'caption='[[9q22]], [[Resolution|resolution]] 3.41Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9q22]] is a 3 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=9Q22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Q22 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.406Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CNP:(3S)-3-[5-(1-benzyl-4-hydroxypiperidin-4-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione'>A1CNP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=9q22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9q22 OCA], [https://pdbe.org/9q22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9q22 RCSB], [https://www.ebi.ac.uk/pdbsum/9q22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9q22 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DDB1_HUMAN DDB1_HUMAN] Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.<ref>PMID:12732143</ref> <ref>PMID:15448697</ref> <ref>PMID:14739464</ref> <ref>PMID:15882621</ref> <ref>PMID:16260596</ref> <ref>PMID:16482215</ref> <ref>PMID:17079684</ref> <ref>PMID:16407242</ref> <ref>PMID:16407252</ref> <ref>PMID:16678110</ref> <ref>PMID:16940174</ref> <ref>PMID:17041588</ref> <ref>PMID:16473935</ref> <ref>PMID:18593899</ref> <ref>PMID:18381890</ref> <ref>PMID:18332868</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Cullin-RING Ligase 4 Cereblon (CRL4(CRBN)) (CRBN) E3 ligase modulatory drugs (CELMoDs(TM)) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDs(TM)) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1alpha, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues. | ||
| - | + | Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues.,Luchini G, Liu S, Powers HL, Cherney E, Zhu J, Danga K, Thompson JW, Shi L, Pagarigan B, Wei DD, Park P, Degnan AP, Zapf CW, Riggs JR, Johnson S, Cummins T J Med Chem. 2025 Sep 25. doi: 10.1021/acs.jmedchem.5c01919. PMID:40994183<ref>PMID:40994183</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9q22" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Pagarigan BE]] | ||
| + | [[Category: Tran ET]] | ||
| + | [[Category: Zhu J]] | ||
Revision as of 06:00, 1 October 2025
Crystal structure of ternary complex Helios-ZF2:I-19:CRBN:DDB1
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