5Y4Q

Crystal structure of Trypanosoma cruzi spermidine synthase in complex with N-(4-methoxyphenyl)quinolin-4-amine

5Y4Q の概要

• エントリーDOI: 10.2210/pdb5y4q/pdb
• 分子名称: Spermidine synthase, putative, 5'-[(S)-(3-AMINOPROPYL)(METHYL)-LAMBDA~4~-SULFANYL]-5'-DEOXYADENOSINE, N-(4-methoxyphenyl)quinolin-4-amine, ... (4 entities in total)
• 機能のキーワード: polyamine synthesis, transferase
• 由来する生物種: Trypanosoma cruzi (strain CL Brener)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 138841.85

構造登録者

Amano, Y.,Tateishi, Y. (登録日: 2017-08-04, 公開日: 2018-08-08, 最終更新日: 2023-12-06)

主引用文献

Yoshino, R.,Yasuo, N.,Hagiwara, Y.,Ishida, T.,Inaoka, D.K.,Amano, Y.,Tateishi, Y.,Ohno, K.,Namatame, I.,Niimi, T.,Orita, M.,Kita, K.,Akiyama, Y.,Sekijima, M.
Discovery of a Hidden Trypanosoma cruzi Spermidine Synthase Binding Site and Inhibitors through In Silico, In Vitro , and X-ray Crystallography.
Acs Omega, 8:25850-25860, 2023

PubMed Abstract: In drug discovery research, the selection of promising binding sites and understanding the binding mode of compounds are crucial fundamental studies. The current understanding of the proteins-ligand binding model extends beyond the simple lock and key model to include the induced-fit model, which alters the conformation to match the shape of the ligand, and the pre-existing equilibrium model, selectively binding structures with high binding affinity from a diverse ensemble of proteins. Although methods for detecting target protein binding sites and virtual screening techniques using docking simulation are well-established, with numerous studies reported, they only consider a very limited number of structures in the diverse ensemble of proteins, as these methods are applied to a single structure. Molecular dynamics (MD) simulation is a method for predicting protein dynamics and can detect potential ensembles of protein binding sites and hidden sites unobservable in a single-point structure. In this study, to demonstrate the utility of virtual screening with protein dynamics, MD simulations were performed on spermidine synthase to obtain an ensemble of dominant binding sites with a high probability of existence. The structure of the binding site obtained through MD simulation revealed pockets in addition to the active site that was present in the initial structure. Using the obtained binding site structures, virtual screening of 4.8 million compounds by docking simulation, assays, and X-ray analysis was conducted, successfully identifying two hit compounds.

PubMed: 37521650
DOI: 10.1021/acsomega.3c01314

実験手法

X-RAY DIFFRACTION (2.07 Å)