9CDV

Crystal Structure of Rhombotarget A

9CDV の概要

• エントリーDOI: 10.2210/pdb9cdv/pdb
• 分子名称: Rhombotarget A, MAGNESIUM ION, 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• 機能のキーワード: de novo design, deep learning, membrane protein, cyclic peptide
• 由来する生物種: Acinetobacter terrae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 101416.14

構造登録者

Bera, A.K.,Rettie, S.,Kang, A.,Bhardwaj, G. (登録日: 2024-06-25, 公開日: 2025-07-02, 最終更新日: 2025-12-10)

主引用文献

Rettie, S.A.,Juergens, D.,Adebomi, V.,Bueso, Y.F.,Zhao, Q.,Leveille, A.N.,Liu, A.,Bera, A.K.,Wilms, J.A.,Uffing, A.,Kang, A.,Brackenbrough, E.,Lamb, M.,Gerben, S.R.,Murray, A.,Levine, P.M.,Schneider, M.,Vasireddy, V.,Ovchinnikov, S.,Weiergraber, O.H.,Willbold, D.,Kritzer, J.A.,Mougous, J.D.,Baker, D.,DiMaio, F.,Bhardwaj, G.
Accurate de novo design of high-affinity protein-binding macrocycles using deep learning.
Nat.Chem.Biol., 21:1948-1956, 2025

PubMed Abstract: Developing macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource intensive and provide little control over binding mode. Despite progress in protein design, there are currently no robust approaches for de novo design of protein-binding macrocycles. Here we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic binders against protein targets of interest. We tested 20 or fewer designed macrocycles against each of four diverse proteins and obtained binders with medium to high affinity against all targets. For one of the targets, Rhombotarget A (RbtA), we designed a high-affinity binder (K < 10 nM) despite starting from the predicted target structure. X-ray structures for macrocycle-bound myeloid cell leukemia 1, γ-aminobutyric acid type A receptor-associated protein and RbtA complexes match closely with the computational models, with a Cα root-mean-square deviation < 1.5 Å to the design models. RFpeptides provides a framework for rapid and custom design of macrocyclic peptides for diagnostic and therapeutic applications.

PubMed: 40542165
DOI: 10.1038/s41589-025-01929-w

実験手法

X-RAY DIFFRACTION (2 Å)