Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid

Article Article scientifique Article Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid eng 2026-05-11 2026-05-19 author Elsner Christina Mareike 0009-0009-0456-7745 Department of Physical Chemistry, University of Geneva, Geneva 1211, Switzerland. 978657 Chimie physique (groupe 9) (CHIF9) author Hanke Anton Ariel 0000-0001-9552-1201 Department of Pharmaceutical Sciences, University of Geneva, Geneva 1211, Switzerland.,Swiss institute of Bioinformatics, University of Geneva. 402307 Section des sciences pharmaceutiques (FARMA) author Vadas Oscar 0000-0003-3511-6479 Department of Microbiology and Molecular Medicine, University of Geneva. 508966 Département de microbiologie et médecine moléculaire (MIMOL) author Gervasio Francesco Luigi 0000-0003-4831-5039 Department of Pharmaceutical Sciences, University of Geneva, Geneva 1211, Switzerland.,Swiss institute of Bioinformatics, University of Geneva.,Department of Chemistry, University College London, London WC1E 6BT, United Kingdom. 931636 Section des sciences pharmaceutiques (FARMA) author Bordignon Enrica 0000-0003-2450-5161 Department of Physical Chemistry, University of Geneva, Geneva 1211, Switzerland. 973830 Département de chimie physique (CHIFI) e2527963123 10.1073/pnas.2527963123 42113980 0027-8424 PMC13187722 https://pnas.org/doi/10.1073/pnas.2527963123 Intrinsic apoptosis is a form of cell death which is activated, executed, and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structural model of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing interresidue distances and dynamic solvent accessibilities complemented by integrative modeling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBid's C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis. Bcl-2 proteins DEER MD simulations Apoptosis Mitochondria Dewey 540 Dewey 615 Dewey 616 Swiss National Science Foundation MITOpore 216587 CH Swiss National Science Foundation Understanding and Modelling Cryptic Binding Pockets for Biology and Drug Discovery 204795 CH 38 Département de chimie physique 142 31 Section des sciences pharmaceutiques 17 54 Département de microbiologie et médecine moléculaire 21B false 443 Biologie d'un parasite intracellulaire obligatoire 773 1362 Modélisation biomoléculaire et pharmaceutique 1428 Groupe Bordignon https://doi.org/10.5281/zenodo.16941554 Proceedings of the National Academy of Sciences of the United States of America 123 20 cce22480-8af6-4f99-9d45-cf369e4c8ab4 Article (Published version) Public elsner-et-al-2026-structural-and-dy.pdf 4280387 application/pdf CC BY-NC-ND-4.0 4f290b0499bbcf22f62c82033cab5388abab20f615e6a431dd8f0a8f5731e512 openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie physique Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire

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Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid	Proceedings of the National Academy of Sciences of the United States of America			2026	1	0

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