3k74

Disruption of protein dynamics by an allosteric effector antibody

spinqualitylabelsall models 3k74, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3k74 is a 2 chain structure with sequence from Escherichia coli K-12 and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å 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 Although it has been known for many years that antibodies display properties characteristic of allosteric effectors, the molecular mechanisms responsible for these effects remain poorly understood. Here, we describe a single-domain antibody fragment (nanobody) that modulates protein function by constraining conformational change in the enzyme dihydrofolate reductase (DHFR). Nanobody 216 (Nb216) behaves as a potent allosteric inhibitor of DHFR, giving rise to mixed hyperbolic inhibition kinetics. The crystal structure of Nb216 in complex with DHFR reveals that the nanobody binds adjacent to the active site. Half of the epitope consists of residues from the flexible Met20 loop. This loop, which ordinarily oscillates between occluded and closed conformations during catalysis, assumes the occluded conformation in the Nb216-bound state. Using stopped flow, we show that Nb216 inhibits DHFR by stabilising the occluded Met20 loop conformation. Surprisingly, kinetic data indicate that the Met20 loop retains sufficient conformational flexibility in the Nb216-bound state to allow slow substrate turnover to occur. Constraining enzyme conformational change by an antibody leads to hyperbolic inhibition.,Oyen D, Srinivasan V, Steyaert J, Barlow JN J Mol Biol. 2011 Mar 18;407(1):138-48. Epub 2011 Jan 14. PMID:21238460 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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