4OQ7

Predicting protein conformational response in prospective ligand discovery.

Summary for 4OQ7

• Entry DOI: 10.2210/pdb4oq7/pdb
• Descriptor: Cytochrome c peroxidase, PROTOPORPHYRIN IX CONTAINING FE (3 entities in total)
• Functional Keywords: model system, energy penalty, boltzmann weights, flexible docking, 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: 2014-02-07, release date: 2014-02-26, 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

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: 24950326
DOI: 10.1038/nchem.1954

Experimental method

X-RAY DIFFRACTION (1.89 Å)