biostudies-literatureTang SXLudwig Center at HarvardNICHD NIH HHSNIA NIH HHSNHLBI NIH HHSAlex's Lemonade Stand Foundation for Childhood CancerNihon Kohden AmericaWood Family FoundationNCI NIH HHSNational Institutes of HealthCook Family FoundationAbell Foundation1815-1826.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC11490406biostudies-literatureUnknown31(10)BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified sCell chemical biologyDissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor.PMC11490406R50 CA211399K00AG078230R50CA211399T32 HL007574K00 AG0782305T32HL007574R35 CA197583P50 HD105351R01 CA205255R01CA205255R35CA197583Tang SXFranco JACamara CMLi YGodes MBird GHWalensky LDMoyer BMSegal RAPazyra-Murphy MFfalseDissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor.BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified s2024-01-01T00:00:00Z2024 Oct2026-06-04T13:56:33.184Z2026-05-10T03:11:22.797ZS-EPMC114904063906744810.1016/j.chembiol.2024.06.016