9VM0

Crystal structure of computational designed protein CSD101

9VM0 の概要

• エントリーDOI: 10.2210/pdb9vm0/pdb
• 分子名称: CSD101 (2 entities in total)
• 機能のキーワード: kinase, cell signalling, map kinase pathway, signaling protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42041.16

構造登録者

Sandholu, A.S.,Siba, A.,Arold, S.T. (登録日: 2025-06-27, 公開日: 2026-07-15, 最終更新日: 2026-07-29)

主引用文献

Talley, J.P.,Stern, J.A.,Alharbi, S.,Green, T.P.,Sandholu, A.,Argyle, M.,Heaps, W.P.,Chipman, D.,Bundy, B.C.,Arold, S.T.,Della Corte, D.
Conformation-Specific Design: Engineering Extracellular Signal-Regulated Kinase 2 Variants with Bias toward Active or Inactive States.
Acs Omega, 11:28717-28724, 2026

PubMed Abstract: Machine learning is revolutionizing protein design by enabling the rapid generation of sequences with precise structural and functional properties. Controlling protein conformational states remains a major challenge, particularly for enzymes regulated by complex structural switches. Here, using high-resolution structural data and probabilistic sequence-structure models, a machine learning-driven framework for conformationally biased protein design is presented titled Conformation-Specific Design or CSDesign. This approach generates sequences predicted to favor a desired conformation while disfavoring alternative states. As a proof-of-concept, this approach is applied to extracellular signal-regulated kinase 2 (ERK2), generating variants predicted to favor the active or inactive state. Experimental validation of relative kinase activity in a controlled assay confirmed that an active-biased variant, CSD104, exhibits robust kinase activity without native upstream phosphorylation, while an inactive-biased variant, CSD101, remains inactivated. Structural analysis suggests that engineered interactions stabilize active-like features in place of phosphorylation. These results demonstrate machine learning control of protein conformational ensembles, with potential to design enzymes and other conformationally regulated proteins without relying on phosphomimetic mutations or extensive experimental screening.

PubMed: 42179606
DOI: 10.1021/acsomega.6c01185

実験手法

X-RAY DIFFRACTION (1.9 Å)