5UUM

Human Mcl-1 in complex with a Bfl-1-specific selected peptide

Summary for 5UUM

• Entry DOI: 10.2210/pdb5uum/pdb
• Related: 5UUK 5UUL 5UUP
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Bfl-1 specific peptide FS2, ZINC ION, ... (5 entities in total)
• Functional Keywords: apoptosis regulatory proteins, peptide library, protein binding, protein structure, proto-oncogene, specificity, bcl2a1, bcl2 related protein a1, peptide inhibitor, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 41665.83

Authors

Jenson, J.M.,Grant, R.A.,Keating, A.E. (deposition date: 2017-02-17, release date: 2017-06-21, Last modification date: 2024-10-16)

Primary citation

Jenson, J.M.,Ryan, J.A.,Grant, R.A.,Letai, A.,Keating, A.E.
Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.
Elife, 6:-, 2017

PubMed Abstract: Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.

PubMed: 28594323
DOI: 10.7554/eLife.25541

Experimental method

X-RAY DIFFRACTION (2.346 Å)