Crystallographic studies of two variants of Pseudomonas aeruginosa IMPDH with impaired allosteric regulation.
Inosine-5'-monophosphate dehydrogenases (IMPDHs), which are the rate-limiting enzymes in guanosine-nucleotide biosynthesis, are important therapeutic targets. Despite in-depth functional and structural characterizations of various IMPDHs, the role of the Bateman domain containing two CBS motifs remains controversial. Their involvement in the allosteric regulation of Pseudomonas aeruginosa IMPDH by Mg-ATP has recently been reported. To better understand the function of IMPDH and the importance of the CBS motifs, the structure of a variant devoid of these modules (ΔCBS) was solved at high resolution in the apo form and in complex with IMP. In addition, a single amino-acid substitution variant, D199N, was also structurally characterized: the mutation corresponds to the autosomal dominant mutant D226N of human IMPDH1, which is responsible for the onset of the retinopathy adRP10. These new structures shed light onto the possible mechanism of regulation of the IMPDH enzymatic activity. In particular, three conserved loops seem to be key players in this regulation as they connect the tetramer-tetramer interface with the active site and show significant modification upon substrate binding.
CNRS, UMR5048, Université Montpellier 1 et 2, Centre de Biochimie Structurale, 34090 Montpellier, France.
Gilles
G
Labesse
Unité de Chimie et Biocatalyse, Institut Pasteur, 75015 Paris, France.
Thomas
T
Alexandre
CNRS, UMR5048, Université Montpellier 1 et 2, Centre de Biochimie Structurale, 34090 Montpellier, France.
Muriel
M
Gelin
Plateforme de Cristallographie, Département de Biologie Structurale et Chimie, Institut Pasteur, 75015 Paris, France.
Ahmed
A
Haouz
Unité de Chimie et Biocatalyse, Institut Pasteur, 75015 Paris, France.
Hélène
H
Munier-Lehmann
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D007168:IMP Dehydrogenase / Q000737:chemistry*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid
D007168:IMP Dehydrogenase
CBS module; IMPDH; allosteric regulation; nucleotide metabolism; quaternary structure