A molecular mechanism for pyrimidine and purine nucleotide control of aspartate transcarbamoylase

Abstract

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 turners together by 0.3 Å in the R state; ATP pushes the regulatory dimers apart by 0.3 Å 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 Å 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.