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TitleMgATP regulates allostery and fiber formation in IMPDHs.
Journal, issue, pagesStructure, Vol. 21, Issue 6, Page 975-985, Year 2013
Publish dateJun 4, 2013
AuthorsGilles Labesse / Thomas Alexandre / Laurène Vaupré / Isabelle Salard-Arnaud / Joséphine Lai Kee Him / Bertrand Raynal / Patrick Bron / Hélène Munier-Lehmann /
PubMed AbstractInosine-5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in nucleotide biosynthesis studied as an important therapeutic target and its complex functioning in vivo is still puzzling ...Inosine-5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in nucleotide biosynthesis studied as an important therapeutic target and its complex functioning in vivo is still puzzling and debated. Here, we highlight the structural basis for the regulation of IMPDHs by MgATP. Our results demonstrate the essential role of the CBS tandem, conserved among almost all IMPDHs. We found that Pseudomonas aeruginosa IMPDH is an octameric enzyme allosterically regulated by MgATP and showed that this octameric organization is widely conserved in the crystal structures of other IMPDHs. We also demonstrated that human IMPDH1 adopts two types of complementary octamers that can pile up into isolated fibers in the presence of MgATP. The aggregation of such fibers in the autosomal dominant mutant, D226N, could explain the onset of the retinopathy adRP10. Thus, the regulatory CBS modules in IMPDHs are functional and they can either modulate catalysis or macromolecular assembly.
External linksStructure / PubMed:23643948
MethodsEM (single particle) / X-ray diffraction
Resolution2.51 - 16.0 Å
Structure data

EMDB-2069:
Octameric structure of IMPDH from Pseudomonas aeruginosa in its APO form
Method: EM (single particle) / Resolution: 15.5 Å

EMDB-2070:
Octameric structure of IMPDH from Pseudomonas aeruginosa in presence of Mg-ATP
Method: EM (single particle) / Resolution: 16.0 Å

PDB-4dqw:
Crystal Structure Analysis of PA3770
Method: X-RAY DIFFRACTION / Resolution: 2.51 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MN:
Unknown entry

ChemComp-PO4:
PHOSPHATE ION

ChemComp-GOL:
GLYCEROL

ChemComp-HOH:
WATER

Source
  • pseudomonas aeruginosa (bacteria)
KeywordsOXIDOREDUCTASE / IMPDH enzyme

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