6mcy
Crystal structure of mouse Bak
Structural highlights
FunctionBAK_MOUSE In the presence of an appropriate stimulus, accelerates programmed cell death by binding to, and antagonizing the anti-apoptotic action of BCL2 (By similarity). Publication Abstract from PubMedActivating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.,van Delft MF, Chappaz S, Khakham Y, Bui CT, Debrincat MA, Lowes KN, Brouwer JM, Grohmann C, Sharp PP, Dagley LF, Li L, McArthur K, Luo MX, Chin HS, Fairlie WD, Lee EF, Segal D, Duflocq S, Lessene R, Bernard S, Peilleron L, Nguyen T, Miles C, Wan SS, Lane RM, Wardak A, Lackovic K, Colman PM, Sandow JJ, Webb AI, Czabotar PE, Dewson G, Watson KG, Huang DCS, Lessene G, Kile BT Nat Chem Biol. 2019 Nov;15(11):1057-1066. doi: 10.1038/s41589-019-0365-8. Epub, 2019 Oct 7. PMID:31591564[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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