4NVA
Predicting protein conformational response in prospective ligand discovery
Summary for 4NVA
| Entry DOI | 10.2210/pdb4nva/pdb |
| Related | 4NVB 4NVC 4NVD 4NVE 4NVF 4NVG 4NVH 4NVI 4NVJ 4NVK 4NVL 4NVM 4NVN 4NVO |
| Descriptor | Cytochrome c peroxidase, PROTOPORPHYRIN IX CONTAINING FE (3 entities in total) |
| Functional Keywords | model system, flexibility, dynamic, loop, side-chains, energy penalty, occupancy, boltzmann weights, flexible docking, ligand binding, oxidoreductase |
| Biological source | Saccharomyces cerevisiae (Baker's yeast) |
| Total number of polymer chains | 1 |
| Total formula weight | 33545.07 |
| Authors | Fischer, M.,Fraser, J.S. (deposition date: 2013-12-05, release date: 2013-12-18, Last modification date: 2024-02-28) |
| Primary citation | Fischer, M.,Coleman, R.G.,Fraser, J.S.,Shoichet, B.K. Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery. Nat Chem, 6:575-583, 2014 Cited by PubMed Abstract: Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available. PubMed: 24950326DOI: 10.1038/nchem.1954 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.57 Å) |
Structure validation
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