8I8Y

A mutant of the C-terminal complex of proteins 4.1G and NuMA

8I8Y の概要

• エントリーDOI: 10.2210/pdb8i8y/pdb
• 分子名称: Engineered protein (2 entities in total)
• 機能のキーワード: a computational design mutant of a fusion protein from the c terminal of 4.1g and numa, de novo protein
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16392.75

構造登録者

Hu, X. (登録日: 2023-02-06, 公開日: 2023-04-19, 最終更新日: 2024-11-20)

主引用文献

Hu, X.,Xu, Y.,Wang, C.,Liu, Y.,Zhang, L.,Zhang, J.,Wang, W.,Chen, Q.,Liu, H.
Combined prediction and design reveals the target recognition mechanism of an intrinsically disordered protein interaction domain.
Proc.Natl.Acad.Sci.USA, 120:e2305603120-e2305603120, 2023

PubMed Abstract: An increasing number of protein interaction domains and their targets are being found to be intrinsically disordered proteins (IDPs). The corresponding target recognition mechanisms are mostly elusive because of challenges in performing detailed structural analysis of highly dynamic IDP-IDP complexes. Here, we show that by combining recently developed computational approaches with experiments, the structure of the complex between the intrinsically disordered C-terminal domain (CTD) of protein 4.1G and its target IDP region in NuMA can be dissected at high resolution. First, we carry out systematic mutational scanning using dihydrofolate reductase-based protein complementarity analysis to identify essential interaction regions and key residues. The results are found to be highly consistent with an α/β-type complex structure predicted by AlphaFold2 (AF2). We then design mutants based on the predicted structure using a deep learning protein sequence design method. The solved crystal structure of one mutant presents the same core structure as predicted by AF2. Further computational prediction and experimental assessment indicate that the well-defined core structure is conserved across complexes of 4.1G CTD with other potential targets. Thus, we reveal that an intrinsically disordered protein interaction domain uses an α/β-type structure module formed through synergistic folding to recognize broad IDP targets. Moreover, we show that computational prediction and experiment can be jointly applied to segregate true IDP regions from the core structural domains of IDP-IDP complexes and to uncover the structure-dependent mechanisms of some otherwise elusive IDP-IDP interactions.

PubMed: 37722056
DOI: 10.1073/pnas.2305603120

実験手法

X-RAY DIFFRACTION (2.9 Å)