6E3I

Human Bfl-1 in complex with the Bfl-1-specific designed peptide srt.F4

6E3I の概要

• エントリーDOI: 10.2210/pdb6e3i/pdb
• 分子名称: Bcl-2-related protein A1, peptide srt.F4, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: anti-apoptotic bcl-2, inhibitor, design, apoptosis
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 19877.60

構造登録者

Jenson, J.M.,Keating, A.E. (登録日: 2018-07-14, 公開日: 2018-10-17, 最終更新日: 2020-01-01)

主引用文献

Jenson, J.M.,Xue, V.,Stretz, L.,Mandal, T.,Reich, L.L.,Keating, A.E.
Peptide design by optimization on a data-parameterized protein interaction landscape.
Proc. Natl. Acad. Sci. U.S.A., 115:E10342-E10351, 2018

PubMed Abstract: Many applications in protein engineering require optimizing multiple protein properties simultaneously, such as binding one target but not others or binding a target while maintaining stability. Such multistate design problems require navigating a high-dimensional space to find proteins with desired characteristics. A model that relates protein sequence to functional attributes can guide design to solutions that would be hard to discover via screening. In this work, we measured thousands of protein-peptide binding affinities with the high-throughput interaction assay amped SORTCERY and used the data to parameterize a model of the alpha-helical peptide-binding landscape for three members of the Bcl-2 family of proteins: Bcl-x, Mcl-1, and Bfl-1. We applied optimization protocols to explore extremes in this landscape to discover peptides with desired interaction profiles. Computational design generated 36 peptides, all of which bound with high affinity and specificity to just one of Bcl-x, Mcl-1, or Bfl-1, as intended. We designed additional peptides that bound selectively to two out of three of these proteins. The designed peptides were dissimilar to known Bcl-2-binding peptides, and high-resolution crystal structures confirmed that they engaged their targets as expected. Excellent results on this challenging problem demonstrate the power of a landscape modeling approach, and the designed peptides have potential uses as diagnostic tools or cancer therapeutics.

PubMed: 30322927
DOI: 10.1073/pnas.1812939115

実験手法

X-RAY DIFFRACTION (1.481 Å)