3qyo | pdb_00003qyo

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

spinqualitylabelsall models 3qyo, resolution 2.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qyo is a 1 chain structure with sequence from Escherichia coli k-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, NDP, Q24 Related: 3qyl Activity: Dihydrofolate reductase, with EC number 1.5.1.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DYR_ECOLI] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMed 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. Evidence for dynamics in proteins as a mechanism for ligand dissociation.,Carroll MJ, Mauldin RV, Gromova AV, Singleton SF, Collins EJ, Lee AL Nat Chem Biol. 2012 Jan 15;8(3):246-52. doi: 10.1038/nchembio.769. PMID:22246400 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase

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