Abstract
Understanding the relationship between protein sequence and structure well enough to design new proteins with desired functions is a longstanding goal in protein science. Here, we show that recurring tertiary structural motifs (TERMs) in the PDB provide rich information for protein-peptide interaction prediction and design. TERM statistics can be used to predict peptide binding energies for Bcl-2 family proteins as accurately as widely used structure-based tools. Furthermore, design using TERM energies (dTERMen) rapidly and reliably generates high-affinity peptide binders of anti-apoptotic proteins Bfl-1 and Mcl-1 with just 15%-38% sequence identity to any known native Bcl-2 family protein ligand. High-resolution structures of four designed peptides bound to their targets provide opportunities to analyze the strengths and limitations of the computational design method. Our results support dTERMen as a powerful approach that can complement existing tools for protein engineering.
Keywords:
BH3 motif; Bcl-2 proteins; apoptosis; inhibitor; interaction specificity; protein-protein interactions; structure-based design; tertiary motif.
Copyright © 2019 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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Binding Sites
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Cloning, Molecular
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Crystallography, X-Ray
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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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Minor Histocompatibility Antigens / chemistry*
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Minor Histocompatibility Antigens / genetics
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Minor Histocompatibility Antigens / metabolism
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Molecular Docking Simulation
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Peptides / chemistry*
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Peptides / genetics
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Peptides / metabolism
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Engineering
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Protein Interaction Domains and Motifs
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Protein Structure, Tertiary
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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
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Sequence Alignment
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Structure-Activity Relationship
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Thermodynamics
Substances
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BCL2-related protein A1
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MCL1 protein, human
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Peptides
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins