7HHS
PanDDA analysis group deposition -- Crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with AVI-0000411
This is a non-PDB format compatible entry.
Summary for 7HHS
| Entry DOI | 10.2210/pdb7hhs/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) |
| Descriptor | Non-structural protein 3, 1-({6-[(1H-indazol-5-yl)amino]pyrimidin-4-yl}amino)pyrrolidin-2-one (3 entities in total) |
| Functional Keywords | macrodomain, adp-ribose, sars-cov-2, fragment-based drug discovery, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 36976.18 |
| Authors | |
| Primary citation | 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 Cited by 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: 40586518DOI: 10.7554/eLife.103797 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (0.98 Å) |
Structure validation
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