In our studies of relationships of biological function to three dimensional geometrical and electronic structures, we are working on the allosteric mechanisms of aspartate transcarbamylase. Having solved the unliganded structure to 3 A resolution, and the structure bound to cytidine triphosphate to 2.8 A resolution, we have improved the diffraction phases, and begun a series of studies of derivatives. We now have difference maps of both ATP and CTP from both crystal forms, showing the near identity of binding of these competitive ligands which, respectively, activate or inhibit the enzyme. Also, some 25,000 unique X-ray maxima have been measured on the enzyme liganded to an antitumor agent N-phosphonacetyl-L-aspartate (PALA), and on a Pt derivative. Search for other heavy atom derivatives continues. This active form of the enzyme has D3 molecular symmetry, and is more elongated along the three-fold axis than are the forms without PALA. Chemical and sequence studies of side chains which modify activity and regulation of this enzyme are continuing. We are also continuing X-ray diffraction studies of cyclic peptides and other molecules, and theoretical studies of molecular orbitals in enzyme models, cofactors and other biologically active compounds. Here, we hope to evaluate the several factors which are responsible for regulation, and for the extraordinarily efficient catalytic powers of enzymes.
NIH ExPorter
NIH ExPorter