Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design

TY - JOUR

T1 - Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design

AU - Brouwer, Jason M.

AU - Lan, Ping

AU - Cowan, Angus D.

AU - Bernardini, Jonathan P.

AU - Birkinshaw, Richard W.

AU - van Delft, Mark F.

AU - Sleebs, Brad E.

AU - Robin, Adeline Y.

AU - Wardak, Ahmad

AU - Tan, Iris K.

AU - Reljic, Boris

AU - Lee, Erinna F.

AU - Fairlie, W. Douglas

AU - Call, Melissa J.

AU - Smith, Brian J.

AU - Dewson, Grant

AU - Lessene, Guillaume

AU - Colman, Peter M.

AU - Czabotar, Peter E.

N1 - Funding Information: We thank Janet Newman and colleagues at the CSIRO C3 crystallization facility; Matthew Call for discussions; Jai Rautela, Mike Ryan, David Huang, David Segal, Sweta Iyer, and Michael Dengler for reagents and technical assistance; and Natasha Ritchie for proofreading the manuscript. This research was undertaken in part using the MX1 and MX2 crystallography beamlines at the Australian Synchrotron, Victoria, Australia, and made use of the ACRF Detector. P.E.C., G.L., and P.M.C. acknowledge NHMRC Fellowships ( 1079700 , 1117089 , 1116934 ). Our work is supported by NHMRC (Australia; Projects Grants 1079706 and 1059290 and Program Grant 1113133 ), the Australian Cancer Research Foundation , the Leukemia and Lymphoma Society (U.S.) (SCOR grant 7001-03 ), the Victorian State Government Operational Infrastructure Support , the Australian Government NHMRC IRIISS , and we acknowledge the support of the Walter and Eliza Hall Institute through the Catalyst Fund . Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/11/16

Y1 - 2017/11/16

N2 - Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation. Brouwer et al. describe the first crystal structures of BH3-only peptides bound to Bak, which reveal a cavity that may be important for activation. They then use structure-based design to alter the Bim-BH3 peptide and convert it from an activator to an inhibitor of Bak.

AB - Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation. Brouwer et al. describe the first crystal structures of BH3-only peptides bound to Bak, which reveal a cavity that may be important for activation. They then use structure-based design to alter the Bim-BH3 peptide and convert it from an activator to an inhibitor of Bak.

KW - apoptosis

KW - Bak

KW - Bcl-2 family

KW - Bim

KW - inhibitor

KW - non-natural amino acid

UR - https://www.scopus.com/pages/publications/85034779404

U2 - 10.1016/j.molcel.2017.11.001

DO - 10.1016/j.molcel.2017.11.001

M3 - Article

C2 - 29149594

SN - 1097-2765

VL - 68

SP - 659-672.e9

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -