5Y4Q

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

Summary for 5Y4Q

• Entry DOI: 10.2210/pdb5y4q/pdb
• Descriptor: Spermidine synthase, putative, 5'-[(S)-(3-AMINOPROPYL)(METHYL)-LAMBDA~4~-SULFANYL]-5'-DEOXYADENOSINE, N-(4-methoxyphenyl)quinolin-4-amine, ... (4 entities in total)
• Functional Keywords: polyamine synthesis, transferase
• Biological source: Trypanosoma cruzi (strain CL Brener)
• Total number of polymer chains: 4
• Total formula weight: 138841.85

Authors

Amano, Y.,Tateishi, Y. (deposition date: 2017-08-04, release date: 2018-08-08, Last modification date: 2023-12-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.07 Å)