3R33: Evidence For Dynamic Motion In Proteins As A Mechanism For Ligand Dissociation

Citation:
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.
PDB ID: 3R33Download
MMDB ID: 96683
PDB Deposition Date: 2011/3/15
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.09  Å
Source Organism:
Similar Structures:
Biological Unit for 3R33: monomeric; determined by author and by software (PISA)
Molecular Components in 3R33
Label Count Molecule
Protein (1 molecule)
1
Dihydrofolate Reductase(Gene symbol: folA)
Molecule annotation
Chemicals (22 molecules)
1
1
2
1
3
17
4
3
* Click molecule labels to explore molecular sequence information.

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