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TitleDeciphering the allosteric regulation of mycobacterial inosine-5'-monophosphate dehydrogenase.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 6673, Year 2024
Publish dateAug 6, 2024
AuthorsOndřej Bulvas / Zdeněk Knejzlík / Jakub Sýs / Anatolij Filimoněnko / Monika Čížková / Kamila Clarová / Dominik Rejman / Tomáš Kouba / Iva Pichová /
PubMed AbstractAllosteric regulation of inosine 5'-monophosphate dehydrogenase (IMPDH), an essential enzyme of purine metabolism, contributes to the homeostasis of adenine and guanine nucleotides. However, the ...Allosteric regulation of inosine 5'-monophosphate dehydrogenase (IMPDH), an essential enzyme of purine metabolism, contributes to the homeostasis of adenine and guanine nucleotides. However, the precise molecular mechanism of IMPDH regulation in bacteria remains unclear. Using biochemical and cryo-EM approaches, we reveal the intricate molecular mechanism of the IMPDH allosteric regulation in mycobacteria. The enzyme is inhibited by both GTP and (p)ppGpp, which bind to the regulatory CBS domains and, via interactions with basic residues in hinge regions, lock the catalytic core domains in a compressed conformation. This results in occlusion of inosine monophosphate (IMP) substrate binding to the active site and, ultimately, inhibition of the enzyme. The GTP and (p)ppGpp allosteric effectors bind to their dedicated sites but stabilize the compressed octamer by a common mechanism. Inhibition is relieved by the competitive displacement of GTP or (p)ppGpp by ATP allowing IMP-induced enzyme expansion. The structural knowledge and mechanistic understanding presented here open up new possibilities for the development of allosteric inhibitors with antibacterial potential.
External linksNat Commun / PubMed:39107302 / PubMed Central
MethodsEM (single particle)
Resolution2.35 - 3.27 Å
Structure data

17988

8pw3

EMDB-17988, PDB-8pw3:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) apo form
Method: EM (single particle) / Resolution: 2.507 Å

18184

8q65

EMDB-18184, PDB-8q65:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP-bound form
Method: EM (single particle) / Resolution: 2.54 Å

18600

8qqp

EMDB-18600: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+GTP-bound form, compressed
PDB-8qqp: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+GTP-bound form, super-compressed
Method: EM (single particle) / Resolution: 2.35 Å

18601

8qqq

EMDB-18601: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+GTP-bound form, less-compressed
PDB-8qqq: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+GTP-bound form, compressed
Method: EM (single particle) / Resolution: 2.43 Å

18602

8qqr

EMDB-18602: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+ppGpp-bound form, compressed
PDB-8qqr: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+ppGpp-bound form, super-compressed
Method: EM (single particle) / Resolution: 2.73 Å

18604

8qqt

EMDB-18604: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+ppGpp-bound form, less-compressed
PDB-8qqt: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+ppGpp-bound form, compressed
Method: EM (single particle) / Resolution: 2.76 Å

18606

8qqv

EMDB-18606, PDB-8qqv:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+IMP-bound form, extended
Method: EM (single particle) / Resolution: 2.99 Å

18607

8qqw

EMDB-18607, PDB-8qqw:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP-bound form, compressed
Method: EM (single particle) / Resolution: 3.27 Å

18608

8qqx

EMDB-18608, PDB-8qqx:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) ATP+IMP-bound form, half-extended
Method: EM (single particle) / Resolution: 3.01 Å

Chemicals

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

ChemComp-MG:
Unknown entry

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

ChemComp-HOH:
WATER

ChemComp-G4P:
GUANOSINE-5',3'-TETRAPHOSPHATE

ChemComp-IMP:
INOSINIC ACID

Source
  • mycolicibacterium smegmatis mc2 155 (bacteria)
KeywordsOXIDOREDUCTASE / Octamer / Apo enzyme / Purine metabolism / IMPDH / ATP-bound complex / ATP+GTP complex / ATP+ppGpp complex / ATP+IMP complex / ATP complex

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