Evaluating transition state structures of vanadium–phosphatase protein complexes using shape analysis

• Shape analysis evaluated the geometry of V–phosphatase complexes vs. a trigonal bipyramid.
• The shape analysis was superior to an analysis based on the t (tau)-value calculations.
• 5-Coordinate vanadium in protein complexes was trigonal bipyramidal and not square pyramidal.
• The umbrella pathway distortions are observed during phosphoryl group transfer reactions.

Shape analysis of coordination complexes is well-suited to evaluate the subtle distortions in the trigonal bipyramidal (TBPY-5) geometry of vanadium coordinated in the active site of phosphatases and characterized by X-ray crystallography. Recent studies using the tau (τ) analysis support the assertion that vanadium is best described as a trigonal bipyramid, because this geometry is the ideal transition state geometry of the phosphate ester substrate hydrolysis (C.C. McLauchlan, B.J. Peters, G.R. Willsky, D.C. Crans, Coord. Chem. Rev. http://dx.doi.org/10.1016/j.ccr.2014.12.012 ; D.C. Crans, M.L. Tarlton, C.C. McLauchlan, Eur. J. Inorg. Chem. 2014, 4450–4468). Here we use continuous shape measures (CShM) analysis to investigate the structural space of the five-coordinate vanadium–phosphatase complexes associated with mechanistic transformations between the tetrahedral geometry and the five-coordinate high energy TBPY-5 geometry was discussed focusing on the protein tyrosine phosphatase 1B (PTP1B) enzyme. No evidence for square pyramidal geometries was observed in any vanadium–protein complexes. The shape analysis positioned the metal ion and the ligands in the active site reflecting the mechanism of the cleavage of the organic phosphate in a phosphatase. We identified the umbrella distortions to be directly on the reaction path between tetrahedral phosphate and the TBPY-5-types of high-energy species. The umbrella distortions of the trigonal bipyramid are therefore identified as being the most relevant types of transition state structures for the phosphoryl group transfer reactions for phosphatases and this may be related to the possibility that vanadium is an inhibitor for enzymes that support both exploded and five-coordinate transition states.

Shape analysis of coordination complexes was used to evaluate distortions in the trigonal bipyramidal geometry of vanadium coordinated in the X-ray crystallographically-characterized active sites of phosphatases. These studies identified the umbrella distortions to be directly on the reaction path between tetrahedral phosphate and the trigonal bipyramid transition state for the phosphoryl group transfer reactions.Figure optionsDownload as PowerPoint slide