9KEC

Crystal structure of the PIN1 and fragment 25 complex.

これはPDB形式変換不可エントリーです。

9KEC の概要

• エントリーDOI: 10.2210/pdb9kec/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL, N-[(4-fluorophenyl)methyl]-4-oxidanyl-butanamide, ... (5 entities in total)
• 機能のキーワード: cis-trans isomerase, isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19055.05

構造登録者

Xiao, Q.J.,Wu, T.T.,Shu, H.L.,Qin, W.M. (登録日: 2024-11-04, 公開日: 2025-08-27)

主引用文献

Xiao, Q.,Tang, J.,Shu, H.,Wu, T.,Zhang, H.,Wang, W.,Wang, L.,Qin, W.
Uncovering druggable hotspots on Pin1 via X-ray crystallographic fragment screening.
Eur.J.Med.Chem., 299:118048-118048, 2025

PubMed Abstract: Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that specifically recognizes and catalyzes the cis-trans isomerization of pSer/Thr-Pro motifs. It plays a pivotal role in cell cycle regulation, signal transduction, and tumorigenesis. Due to its overexpression in many cancer types, Pin1 has emerged as a promising target for the development of anticancer drugs. However, the relatively shallow and flat surface of Pin1 presents significant challenges for traditional small-molecule inhibitor design. To overcome these limitations, we employed an X-ray crystallography-based fragment screening strategy and identified approximately 50 Pin1-fragment complex structures from a curated fragment library. Systematic structural analysis revealed several druggable binding hotspots, including the well-characterized catalytic center (Site 1) and a neighboring region near the catalytic residue Cys113 (Site 2). Both sites supported stable binding with diverse fragment scaffolds. Notably, several fragments displayed cooperative binding across multiple sites, highlighting their potential as scaffolds for multifunctional inhibitor design. Additionally, a subset of fragments showed reactivity toward Cys113, and their covalent binding modes were confirmed through crystallographic and mass spectrometric analyses. Enzymatic inhibition assays further demonstrated that several fragments effectively suppressed Pin1 activity in solution, validating their potential as lead compounds. In summary, this study systematically mapped functional binding pockets on Pin1 through a structure-driven fragment screening approach, expanded its druggable landscape, and identified key structural features and fragment chemotypes to guide the development of selective, well-defined Pin1 inhibitors.

PubMed: 40803165
DOI: 10.1016/j.ejmech.2025.118048

実験手法

X-RAY DIFFRACTION (1.68 Å)