2AS3

cytochrome c peroxidase in complex with phenol

2AS3 の概要

• エントリーDOI: 10.2210/pdb2as3/pdb
• 関連するPDBエントリー: 1AA4 2ANZ 2AQD 2AS1 2AS2
• 分子名称: Cytochrome c peroxidase, mitochondrial, POTASSIUM ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, peroxidase, model binding site
• 由来する生物種: Saccharomyces cerevisiae (baker's yeast)
• 細胞内の位置: Mitochondrion matrix: P00431
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34207.95

構造登録者

Brenk, R.,Vetter, S.W.,Boyce, S.E.,Goodin, D.B.,Shoichet, B.K. (登録日: 2005-08-22, 公開日: 2006-04-11, 最終更新日: 2023-08-23)

主引用文献

Brenk, R.,Vetter, S.W.,Boyce, S.E.,Goodin, D.B.,Shoichet, B.K.
Probing molecular docking in a charged model binding site.
J.Mol.Biol., 357:1449-1470, 2006

PubMed Abstract: A model binding site was used to investigate charge-charge interactions in molecular docking. This simple site, a small (180A(3)) engineered cavity in cyctochrome c peroxidase (CCP), is negatively charged and completely buried from solvent, allowing us to explore the balance between electrostatic energy and ligand desolvation energy in a system where many of the common approximations in docking do not apply. A database with about 5300 molecules was docked into this cavity. Retrospective testing with known ligands and decoys showed that overall the balance between electrostatic interaction and desolvation energy was captured. More interesting were prospective docking scre"ens that looked for novel ligands, especially those that might reveal problems with the docking and energy methods. Based on screens of the 5300 compound database, both high-scoring and low-scoring molecules were acquired and tested for binding. Out of 16 new, high-scoring compounds tested, 15 were observed to bind. All of these were small heterocyclic cations. Binding constants were measured for a few of these, they ranged between 20microM and 60microM. Crystal structures were determined for ten of these ligands in complex with the protein. The observed ligand geometry corresponded closely to that predicted by docking. Several low-scoring alkyl amino cations were also tested and found to bind. The low docking score of these molecules owed to the relatively high charge density of the charged amino group and the corresponding high desolvation penalty. When the complex structures of those ligands were determined, a bound water molecule was observed interacting with the amino group and a backbone carbonyl group of the cavity. This water molecule mitigates the desolvation penalty and improves the interaction energy relative to that of the "naked" site used in the docking screen. Finally, six low-scoring neutral molecules were also tested, with a view to looking for false negative predictions. Whereas most of these did not bind, two did (phenol and 3-fluorocatechol). Crystal structures for these two ligands in complex with the cavity site suggest reasons for their binding. That these neutral molecules do, in fact bind, contradicts previous results in this site and, along with the alkyl amines, provides instructive false negatives that help identify weaknesses in our scoring functions. Several improvements of these are considered.

PubMed: 16490206
DOI: 10.1016/j.jmb.2006.01.034

実験手法

X-RAY DIFFRACTION (1.4 Å)