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

Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5281-5. doi: 10.1073/pnas.89.12.5281.

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 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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology*
  • Allosteric Site
  • Amino Acid Sequence
  • Aspartate Carbamoyltransferase / chemistry
  • Aspartate Carbamoyltransferase / metabolism*
  • Binding Sites
  • Computer Simulation
  • Cytidine Triphosphate / metabolism
  • Cytidine Triphosphate / pharmacology*
  • Macromolecular Substances
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Conformation

Substances

  • Macromolecular Substances
  • Cytidine Triphosphate
  • Adenosine Triphosphate
  • Aspartate Carbamoyltransferase