7HHV

PanDDA analysis group deposition -- Crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with AVI-0000527

これはPDB形式変換不可エントリーです。

7HHV の概要

• エントリーDOI: 10.2210/pdb7hhv/pdb
• Group deposition: PanDDA analysis group deposition of SARS-CoV-2 NSP3 macrodomain ligand screen - ligands from AVI-219, AVI-249 and AVI-1504 optimization (G_1002307)
• 分子名称: Non-structural protein 3, DIMETHYL SULFOXIDE, (3R)-3-(2,4-difluorophenyl)-3-{[(4R)-[1,2,4]triazolo[1,5-a]pyridine-5-carbonyl]amino}propanoic acid, ... (4 entities in total)
• 機能のキーワード: macrodomain, adp-ribose, sars-cov-2, fragment-based drug discovery, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37284.51

構造登録者

Correy, G.J.,Fraser, J.S. (登録日: 2024-09-16, 公開日: 2025-08-20)

主引用文献

Flowers, J.,Echols, N.,Correy, G.J.,Jaishankar, P.,Togo, T.,Renslo, A.R.,van den Bedem, H.,Fraser, J.S.,Wankowicz, S.A.
Expanding automated multiconformer ligand modeling to macrocycles and fragments.
Elife, 14:-, 2025

PubMed Abstract: Small molecule ligands exhibit a diverse range of conformations in solution. Upon binding to a target protein, this conformational diversity is reduced. However, ligands can retain some degree of conformational flexibility even when bound to a receptor. In the Protein Data Bank, a small number of ligands have been modeled with distinct alternative conformations that are supported by macromolecular X-ray crystallography density maps. However, the vast majority of structural models are fit to a single-ligand conformation, potentially ignoring the underlying conformational heterogeneity present in the sample. We previously developed qFit-ligand to sample diverse ligand conformations and to select a parsimonious ensemble consistent with the density. While this approach indicated that many ligands populate alternative conformations, limitations in our sampling procedures often resulted in non-physical conformations and could not model complex ligands like macrocycles. Here, we introduce several improvements to qFit-ligand, including integrating RDKit for stochastic conformational sampling. This new sampling method greatly enriches low-energy conformations of small molecules and macrocycles. We further extended qFit-ligand to identify alternative conformations in PanDDA-modified density maps from high-throughput X-ray fragment screening experiments, as well as single-particle cryo-electron microscopy density maps. The new version of qFit-ligand improves fit to electron density and reduces torsional strain relative to deposited single-conformer models and our prior version of qFit-ligand. These advances enhance the analysis of residual conformational heterogeneity present in ligand-bound structures, which can provide important insights for the rational design of therapeutic agents.

PubMed: 40586518
DOI: 10.7554/eLife.103797

実験手法

X-RAY DIFFRACTION (1.02 Å)