A5063424737- Cell death mechanisms and regulation
- RNA Interference and Gene Delivery
- Chronic Lymphocytic Leukemia Research
- Enzyme Structure and Function
- interferon and immune responses
- Malaria Research and Control
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- ATP Synthase and ATPases Research
- Phagocytosis and Immune Regulation
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Metal complexes synthesis and properties
- PARP inhibition in cancer therapy
- Computational Drug Discovery Methods
- Signaling Pathways in Disease
- Endoplasmic Reticulum Stress and Disease
- Hippo pathway signaling and YAP/TAZ
- CRISPR and Genetic Engineering
- Cell Adhesion Molecules Research
- Lanthanide and Transition Metal Complexes
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Cancer-related Molecular Pathways
Walter and Eliza Hall Institute of Medical Research
2016-2025
The University of Melbourne
2016-2025
St Andrew's Healthcare
2021-2024
Heidelberg (Poland)
2023-2024
International School of Trieste
2023-2024
FC Barcelona
2023-2024
Hudson Institute
2021-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2021
GTx (United States)
2021
Ashwini Hospital
2014
A central issue in the regulation of apoptosis by Bcl-2 family is whether its BH3-only members initiate directly binding to essential cell-death mediators Bax and Bak, or they can act indirectly, engaging their pro-survival Bcl-2-like relatives. Contrary direct-activation model, we show that Bak mediate without discernable association with putative activators (Bim, Bid, Puma), even cells no Bim Bid reduced Puma. Our results indicate proteins induce at least primarily multiple relatives guarding Bak.
Significance The four-helix bundle (4HB) domain of Mixed Lineage Kinase Domain-Like (MLKL) bears two clusters residues that are required for cell death by necroptosis. Mutations within a cluster centered on the α4 helix 4HB MLKL prevented its membrane translocation, oligomerization, and ability to induce This is composed principally acidic therefore challenges idea engages negatively charged phospholipid membranes via conventional positively interaction surface. importance translocation...
In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify conformational changes that induce oligomerization, we determined crystal structures of BaxΔC21 treated with detergents BH3 peptides. The peptides bound canonical surface groove but, unlike their complexes prosurvival relatives, dissociated into...
Apoptosis is held in check by prosurvival proteins of the Bcl-2 family. The distantly related BH3-only bind to and antagonize them, thereby promoting apoptosis. Whereas binding protein Noxa Mcl-1 induces degradation proteasome, another ligand, Bim, elevates levels. We compared three-dimensional structures complexes formed between BH3 peptides both Bim Noxa, we show that a discrete C-terminal sequence necessary instigate degradation.
Abstract The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, recurs most patients. To investigate the mechanisms secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 CLL enrolled on clinical trials. novel Gly101Val mutation was identified at 7 patients, but not study entry. It first detectable after 19 to 42 months therapy,...
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening structure-based design. This compound is substantially more against BCL-XL-dependent cell lines relative to our recently reported WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused mechanism-based reversible thrombocytopenia in mice inhibited H146 small lung cancer xenograft tumor growth vivo following multiple doses....
Abstract Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia this BCL-2 antagonist has revealed emergence drug-selected mutation (G101V) in some failing therapy. To understand molecular basis acquired resistance we describe crystal structures venetoclax bound to both and G101V mutant. The pose its binding site on reveals small but unexpected differences as...
Necroptotic cell death is mediated by the most terminal known effector of pathway, MLKL. Precisely how phosphorylation MLKL pseudokinase domain activation loop upstream kinase, RIPK3, induces unmasking N-terminal executioner four-helix bundle (4HB) MLKL, higher-order assemblies, and permeabilization plasma membranes remains poorly understood. Here, we reveal existence a basal monomeric conformer present in human cells prior to exposure necroptotic stimulus. Following activation, toggling...