3QYO

Sensitivity of receptor internal motions to ligand binding affinity and kinetic off-rate

3QYO の概要

• エントリーDOI: 10.2210/pdb3qyo/pdb
• 関連するPDBエントリー: 3QYL
• 分子名称: Dihydrofolate reductase, quinazoline-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: rossmann fold, reductase, oxidoreductase
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19246.55

構造登録者

Collins, E.J.,Lee, A.L.,Carroll, M.J.,Mauldin, R.V.,Gromova, A.V.,Singleton, S.F. (登録日: 2011-03-03, 公開日: 2012-01-18, 最終更新日: 2024-02-21)

主引用文献

Carroll, M.J.,Mauldin, R.V.,Gromova, A.V.,Singleton, S.F.,Collins, E.J.,Lee, A.L.
Evidence for dynamics in proteins as a mechanism for ligand dissociation.
Nat.Chem.Biol., 8:246-252, 2012

PubMed Abstract: Signal transduction, regulatory processes and pharmaceutical responses are highly dependent upon ligand residence times. Gaining insight into how physical factors influence residence times (1/k(off)) should enhance our ability to manipulate biological interactions. We report experiments that yield structural insight into k(off) involving a series of eight 2,4-diaminopyrimidine inhibitors of dihydrofolate reductase whose binding affinities vary by six orders of magnitude. NMR relaxation-dispersion experiments revealed a common set of residues near the binding site that undergo a concerted millisecond-timescale switching event to a previously unidentified conformation. The rate of switching from ground to excited conformations correlates exponentially with the binding affinity K(i) and k(off), suggesting that protein dynamics serves as a mechanical initiator of ligand dissociation within this series and potentially for other macromolecule-ligand systems. Although the forward rate of conformational exchange, k(conf,forward), is faster than k(off), the use of the ligand series allowed for connections to be drawn between kinetic events on different timescales.

PubMed: 22246400
DOI: 10.1038/nchembio.769

実験手法

X-RAY DIFFRACTION (2.09 Å)