5W8F

Crystal structure of human Mcl-1 in complex with modified Bim BH3 peptide SAH-MS1-14

Summary for 5W8F

• Entry DOI: 10.2210/pdb5w8f/pdb
• Related: 5W89
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, modified Bim BH3 peptide SAH-MS1-14, ZINC ION, ... (4 entities in total)
• Functional Keywords: stapled peptide, bcl-2 family, bh3 domain, apoptosis, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane ; Single-pass membrane protein : Q07820
• Total number of polymer chains: 2
• Total formula weight: 19874.43

Authors

Rezaei Araghi, R.,Jenson, J.M.,Grant, R.A.,Keating, A.E. (deposition date: 2017-06-21, release date: 2018-01-17, Last modification date: 2024-11-20)

Primary citation

Rezaei Araghi, R.,Bird, G.H.,Ryan, J.A.,Jenson, J.M.,Godes, M.,Pritz, J.R.,Grant, R.A.,Letai, A.,Walensky, L.D.,Keating, A.E.
Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.
Proc. Natl. Acad. Sci. U.S.A., 115:E886-E895, 2018

PubMed Abstract: Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation workflow applicable to a host of challenging biomedical targets.

PubMed: 29339518
DOI: 10.1073/pnas.1712952115

Experimental method

X-RAY DIFFRACTION (1.85 Å)