9REM

Crystal Structure of the Protein-Kinase A catalytic subunit from Cricetulus griseus in complex with F294

これはPDB形式変換不可エントリーです。

9REM の概要

• エントリーDOI: 10.2210/pdb9rem/pdb
• 分子名称: cAMP-dependent protein kinase catalytic subunit alpha, 4-[2-[[(3~{R})-3-oxidanylpyrrolidin-1-yl]methyl]-1,3-thiazol-4-yl]piperidin-4-ol, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: serine-threonine kinase, small molecules, ligand binding, fragment-based drug discovery, transferase
• 由来する生物種: Cricetulus griseus (Chinese hamster)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41865.95

構造登録者

Sandner, A.,Mueller, J.M.,Wolter, M.,Glinca, S.,Klebe, G. (登録日: 2025-06-03, 公開日: 2025-12-31, 最終更新日: 2026-01-07)

主引用文献

Santura, A.,Muller, J.,Wolter, M.,Tutzschky, I.C.,Ruf, M.,Metz, A.,Sandner, A.,Merkl, S.,Klebe, G.,Glinca, S.,Czodrowski, P.
Natural Product-like Fragments Unlock Novel Chemotypes for a Kinase Target─Exploring Options beyond the Flatland.
J.Chem.Inf.Model., 2025

PubMed Abstract: In this study, we utilized a high-performance soaking system of protein kinase A (PKA) to perform a crystallographic screening of a natural product-like fragment library. We resolved 36 fragment-bound structures, corresponding to a hit rate of 41%. Nine fragments bound within the ATP site, nine peripherally, and 18 interacted with both the ATP and peripheral sites. One fragment binds to the same site as the approved allosteric kinase inhibitor asciminib, while another induces an unexpected conformational change. Systematic database mining revealed that both the fragments and their natural product parents have not been previously associated with PKA or kinase activity. A scaffold/chemotype analysis further underscored their novelty. Cheminformatics analyses confirmed that these fragments occupy a distinct chemical space, enriched in saturation, spatial complexity and molecular three-dimensional character compared to kinase binders from reference data sets. These properties have previously been linked to increased selectivity, reduced CYP450 inhibition, and higher overall clinical success rates.

PubMed: 41430555
DOI: 10.1021/acs.jcim.5c01952

実験手法

X-RAY DIFFRACTION (1.43 Å)