5WHH

Crystal Structure of Bcl-2-related protein A1 in complex with stapled peptide (AQ7)T(0EH)LRRFGD(MK8)INFRQ(NH2)

Summary for 5WHH

• Entry DOI: 10.2210/pdb5whh/pdb
• Descriptor: Bcl-2-related protein A1, (AQ7)T(0EH)LRRFGD(MK8)INFRQ(NH2), CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: apoptosis, stapled peptide
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: Q16548
• Total number of polymer chains: 2
• Total formula weight: 20689.99

Authors

Seo, H.-S.,Dhe-Paganon, S. (deposition date: 2017-07-17, release date: 2018-01-17, Last modification date: 2023-11-15)

Primary citation

Harvey, E.P.,Seo, H.S.,Guerra, R.M.,Bird, G.H.,Dhe-Paganon, S.,Walensky, L.D.
Crystal Structures of Anti-apoptotic BFL-1 and Its Complex with a Covalent Stapled Peptide Inhibitor.
Structure, 26:153-160.e4, 2018

PubMed Abstract: BCL-2 family proteins are high-priority cancer targets whose structures provide essential blueprints for drug design. Whereas numerous structures of anti-apoptotic BCL-2 protein complexes with α-helical BH3 peptides have been reported, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69-Å resolution, revealing similarities and key differences among unliganded anti-apoptotic proteins. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by a NOXA BH3-based stapled peptide inhibitor. The crystal structure of this complex demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for therapeutic targeting so that the apoptotic blockades of BFL-1-dependent cancers can be overcome.

PubMed: 29276033
DOI: 10.1016/j.str.2017.11.016

Experimental method

X-RAY DIFFRACTION (2.38 Å)