6MBC

Human Bfl-1 in complex with the designed peptide dF4

Summary for 6MBC

• Entry DOI: 10.2210/pdb6mbc/pdb
• Descriptor: Bcl-2-related protein A1, dF4 (3 entities in total)
• Functional Keywords: anti-apoptotic bcl-2, inhibitor, design, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 20255.22

Authors

Jenson, J.M.,Keating, A.E. (deposition date: 2018-08-29, release date: 2019-03-06, Last modification date: 2024-10-23)

Primary citation

Frappier, V.,Jenson, J.M.,Zhou, J.,Grigoryan, G.,Keating, A.E.
Tertiary Structural Motif Sequence Statistics Enable Facile Prediction and Design of Peptides that Bind Anti-apoptotic Bfl-1 and Mcl-1.
Structure, 27:606-617.e5, 2019

PubMed 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.

PubMed: 30773399
DOI: 10.1016/j.str.2019.01.008

Experimental method

X-RAY DIFFRACTION (1.752 Å)