5uup

Human Bfl-1 covalently cross-linked to an electrophilic variant of a Bfl-1-specific selected peptide

spinqualitylabelsall models 5uup, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5uup is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.726Å Ligands: AKR, NH2, SO4 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 Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors. Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.,Jenson JM, Ryan JA, Grant RA, Letai A, Keating AE Elife. 2017 Jun 8;6. pii: e25541. doi: 10.7554/eLife.25541. PMID:28594323 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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