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.
Keywords:
BCL-2; BCL-2 family; BFL-1/A1; BH3-only protein; BIM; MCL-1; NOXA; apoptosis; covalent inhibitor; stapled peptide.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Apoproteins / antagonists & inhibitors
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Apoproteins / chemistry*
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Apoproteins / genetics
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Apoproteins / metabolism
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Binding Sites
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Cloning, Molecular
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Crystallography, X-Ray
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Humans
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Hydrophobic and Hydrophilic Interactions
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Ligands
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Minor Histocompatibility Antigens / chemistry*
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Minor Histocompatibility Antigens / genetics
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Minor Histocompatibility Antigens / metabolism
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Models, Molecular
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Peptide Fragments / chemical synthesis
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Peptide Fragments / chemistry*
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Proto-Oncogene Proteins / chemical synthesis
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Antineoplastic Agents
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Apoproteins
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BCL2-related protein A1
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Bax protein (53-86)
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Ligands
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Minor Histocompatibility Antigens
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PMAIP1 protein, human
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins