6vo4

Crystal Structure Analysis of BFL1

spinqualitylabelsall models 6vo4, resolution 1.74Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vo4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.74Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also B-cell lymphoma proteins 3D structures

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