5urm
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human BRR2 in complex with T-1206548== | |
| + | <StructureSection load='5urm' size='340' side='right' caption='[[5urm]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5urm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5URM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5URM FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8LV:3-(5-{[(2R)-5-amino-2-cyclohexyl-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-6-yl]methyl}furan-2-yl)benzoic+acid'>8LV</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5urj|5urj]], [[5urk|5urk]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA_helicase RNA helicase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.13 3.6.4.13] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5urm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5urm OCA], [http://pdbe.org/5urm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5urm RCSB], [http://www.ebi.ac.uk/pdbsum/5urm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5urm ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/U520_HUMAN U520_HUMAN]] Retinitis pigmentosa. Retinitis pigmentosa 33 (RP33) [MIM:[http://omim.org/entry/610359 610359]]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:16723661</ref> <ref>PMID:23045696</ref> <ref>PMID:19878916</ref> <ref>PMID:19710410</ref> <ref>PMID:21618346</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/U520_HUMAN U520_HUMAN]] RNA helicase that plays an essential role in pre-mRNA splicing as component of the U5 snRNP and U4/U6-U5 tri-snRNP complexes. Involved in spliceosome assembly, activation and disassembly. Mediates changes in the dynamic network of RNA-RNA interactions in the spliceosome. Catalyzes the ATP-dependent unwinding of U4/U6 RNA duplices, an essential step in the assembly of a catalytically active spliceosome.<ref>PMID:16723661</ref> <ref>PMID:8670905</ref> <ref>PMID:9539711</ref> <ref>PMID:23045696</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2. | ||
| - | + | Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.,Iwatani-Yoshihara M, Ito M, Klein MG, Yamamoto T, Yonemori K, Tanaka T, Miwa M, Morishita D, Endo S, Tjhen R, Qin L, Nakanishi A, Maezaki H, Kawamoto T J Med Chem. 2017 Jul 13;60(13):5759-5771. doi: 10.1021/acs.jmedchem.7b00461. Epub, 2017 Jun 20. PMID:28586220<ref>PMID:28586220</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5urm" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: RNA helicase]] | ||
| + | [[Category: Klein, M G]] | ||
[[Category: Qin, L]] | [[Category: Qin, L]] | ||
[[Category: Tjhen, R]] | [[Category: Tjhen, R]] | ||
| - | [[Category: | + | [[Category: Brr2 inhibitor]] |
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Rna helicase]] | ||
Revision as of 16:15, 20 October 2017
Crystal structure of human BRR2 in complex with T-1206548
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