3QYL
Sensitivity of receptor internal motions to ligand binding affinity and kinetic off-rate
Summary for 3QYL
| Entry DOI | 10.2210/pdb3qyl/pdb |
| Related | 3QYO |
| Descriptor | Dihydrofolate reductase, (7S)-7-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total) |
| Functional Keywords | rossmann fold, reductase, oxidoreductase |
| Biological source | Escherichia coli K-12 |
| Total number of polymer chains | 1 |
| Total formula weight | 19059.59 |
| Authors | Collins, E.J.,Lee, A.L.,Carroll, M.J.,Mauldin, R.V.,Gromova, A.V.,Singleton, S.F. (deposition date: 2011-03-03, release date: 2012-01-18, Last modification date: 2024-02-21) |
| Primary citation | 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 Cited by 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: 22246400DOI: 10.1038/nchembio.769 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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