A molecular mechanism for pyrimidine and purine nucleotide control of aspartate transcarbamoylase.
CTP (ATP) binding to the T or R state causes reorientation of several key residues and results in a decrease (increase) in the size of the nucleotide binding site and a related decrease (increase) in the extension of the outer parts of the dimer of the regulatory chains, R1 and R6. As a result, CTP pinches the regulatory dimers together by 0.3 A in the R state; ATP pushes the regulatory dimers apart by 0.3 A in the T state. These changes influence key residues in the R1-C1 interface of the R state and the R1-C1 and R1-C4 interfaces of the T state, such that the separation of catalytic trimers (c3 ... c3) is decreased by 0.5 A by CTP in the R state and increased by 0.4 A by ATP in the T state. (Smaller effects on c3 ... c3 are observed when CTP binds to the sterically crowded T state or when ATP binds to the elongated R state). These changes reorient key residues in the active site (e.g., catalytic chain residue Arg-229, a residue involved in aspartate binding). This pattern for action of CTP and ATP in perturbing the regulatory dimer, and consequently both the structure and flexibility in critical parts of the T state or R state, is called the nucleotide perturbation mechanism.
Stevens
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Gibbs Chemical Laboratory, Harvard University, Cambridge, MA 02138.
Lipscomb
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D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001221:Aspartate Carbamoyltransferase / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D003570:Cytidine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D046911:Macromolecular Substances; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation
D046911:Macromolecular Substances; D003570:Cytidine Triphosphate; D000255:Adenosine Triphosphate; D001221:Aspartate Carbamoyltransferase