Conformational analysis of an EP24.15 inhibitor by NMR and molecular modelling |
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Authors: | Anderson Rosaleen J Clark Brian P Hewage Chandralal M Smith A Ian Mackay Simon P |
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Institution: | (1) Institute of Pharmacy and Chemistry, School of Health Sciences, University of Sunderland, SR1 3SD Sunderland, U.K.;(2) Department of Chemistry, Edinburgh High Field NMR Centre, University of Edinburgh, EH9 3JJ Edinburgh, U.K.;(3) Peptide Biology Laboratory, Baker Medical Research Institute, 3181 Prahran, Pic, Australia |
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Abstract: | Summary The enzyme thimet oligopeptidase (EC3.4.24.15, EP24.15) is responsible for the hydrolysis of a number of neuropeptides. Despite
much research examining its substrate specificity, little is known about the conformational requirements of its active site.
We have used 1D1H and 2D TOCSY NMR experiments to assign the proton resonances of the EP24.15 inhibitor,N-1-(R, S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), and 2D ROESY NMR to investigate whether cFP exhibits any conformational preferences in CD3OD and in aqueous CD3OD. Molecular modelling of charged cFP in the gaseous phase generated a number of conformations that were consistent with
the NMR data obtained in CD3OD. Analogous modelling on the uncharged cFP did not result in conformations consistent with any of the NMR data, but did
suggest that, under non-polar conditions, cFP could adopt a hairpin conformation which would allow simultaneous coordination
of the two carboxyl groups of cFP to the zinc ion in the active site of EP24.15. |
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Keywords: | cFP conformational analysis dynamics simulations EP24 15 ROESY thimet oligopeptidase |
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