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| | <StructureSection load='6vo4' size='340' side='right'caption='[[6vo4]], [[Resolution|resolution]] 1.74Å' scene=''> | | <StructureSection load='6vo4' size='340' side='right'caption='[[6vo4]], [[Resolution|resolution]] 1.74Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vo4]] is a 1 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=6VO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VO4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vo4]] is a 1 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=6VO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VO4 FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2A1, BCL2L5, BFL1, GRS, HBPA1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.74Å</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=6vo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vo4 OCA], [https://pdbe.org/6vo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vo4 RCSB], [https://www.ebi.ac.uk/pdbsum/6vo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vo4 ProSAT]</span></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=6vo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vo4 OCA], [https://pdbe.org/6vo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vo4 RCSB], [https://www.ebi.ac.uk/pdbsum/6vo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vo4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/B2LA1_HUMAN B2LA1_HUMAN]] Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity).
| + | [https://www.uniprot.org/uniprot/B2LA1_HUMAN B2LA1_HUMAN] Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dhe-Paganon, S]] | + | [[Category: Dhe-Paganon S]] |
| - | [[Category: Seo, H S]] | + | [[Category: Seo H-S]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Bcl-2 family]]
| + | |
| - | [[Category: Bfl-1/a1]]
| + | |
| - | [[Category: Disulfide tethering]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Small molecule]]
| + | |
| Structural highlights
Function
B2LA1_HUMAN Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity).
Publication Abstract from PubMed
The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.
Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.,Harvey EP, Hauseman ZJ, Cohen DT, Rettenmaier TJ, Lee S, Huhn AJ, Wales TE, Seo HS, Luccarelli J, Newman CE, Guerra RM, Bird GH, Dhe-Paganon S, Engen JR, Wells JA, Walensky LD Cell Chem Biol. 2020 Jun 18;27(6):647-656.e6. doi:, 10.1016/j.chembiol.2020.04.004. Epub 2020 May 14. PMID:32413285[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Harvey EP, Hauseman ZJ, Cohen DT, Rettenmaier TJ, Lee S, Huhn AJ, Wales TE, Seo HS, Luccarelli J, Newman CE, Guerra RM, Bird GH, Dhe-Paganon S, Engen JR, Wells JA, Walensky LD. Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering. Cell Chem Biol. 2020 Jun 18;27(6):647-656.e6. doi:, 10.1016/j.chembiol.2020.04.004. Epub 2020 May 14. PMID:32413285 doi:http://dx.doi.org/10.1016/j.chembiol.2020.04.004
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