Deciphering the allosteric regulation of mycobacterial
inosine-5′-monophosphate dehydrogenase

J 2024

Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase

BULVAS, Ondrej; Zdenek KNEJZLIK; Jakub SYS; Anatolij FILIMONENKO; Monika CIZKOVA et. al.

Základní údaje

Originální název

Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase

Autoři

BULVAS, Ondrej; Zdenek KNEJZLIK; Jakub SYS; Anatolij FILIMONENKO; Monika CIZKOVA; Kamila CLAROVA; Dominik REJMAN; Tomas KOUBA a Iva PICHOVA

Vydání

Nature Communications, Berlin, Nature, 2024, 2041-1723

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 15.700

Kód RIV

RIV/00216224:90242/24:00139180

Organizační jednotka

CIISB III

DOI

https://doi.org/10.1038/s41467-024-50933-6

UT WoS

001285374600018

EID Scopus

2-s2.0-85200560912

Klíčová slova anglicky

SMALL-ANGLE SCATTERING;INOSINE MONOPHOSPHATE DEHYDROGENASE; IMP DEHYDROGENASE; CRYO-EM; MECHANISM; INHIBITORS; TOOLS

Štítky

CF CRYO, ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 26. 3. 2025 23:51, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

90242, velká výzkumná infrastruktura

Název: CIISB III

Citovat

BULVAS, Ondrej; Zdenek KNEJZLIK; Jakub SYS; Anatolij FILIMONENKO; Monika CIZKOVA; Kamila CLAROVA; Dominik REJMAN; Tomas KOUBA a Iva PICHOVA. Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase. Nature Communications. Berlin: Nature, 2024, roč. 15, č. 1, s. 1-14. ISSN 2041-1723. Dostupné z: https://doi.org/10.1038/s41467-024-50933-6.

@article{2486919,
   author = {Bulvas, Ondrej and Knejzlik, Zdenek and Sys, Jakub and Filimonenko, Anatolij and Cizkova, Monika and Clarova, Kamila and Rejman, Dominik and Kouba, Tomas and Pichova, Iva},
   article_location = {Berlin},
   article_number = {1},
   doi = {https://doi.org/10.1038/s41467-024-50933-6},
   keywords = {SMALL-ANGLE SCATTERING;INOSINE MONOPHOSPHATE DEHYDROGENASE; IMP DEHYDROGENASE; CRYO-EM; MECHANISM; INHIBITORS; TOOLS},
   language = {eng},
   issn = {2041-1723},
   journal = {Nature Communications},
   title = {Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase},
   url = {https://www.nature.com/articles/s41467-024-50933-6},
   volume = {15},
   year = {2024}
}

TY  - JOUR
ID  - 2486919
AU  - Bulvas, Ondrej - Knejzlik, Zdenek - Sys, Jakub - Filimonenko, Anatolij - Cizkova, Monika - Clarova, Kamila - Rejman, Dominik - Kouba, Tomas - Pichova, Iva
PY  - 2024
TI  - Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase
JF  - Nature Communications
VL  - 15
IS  - 1
SP  - 1-14
EP  - 1-14
PB  - Nature
SN  - 20411723
KW  - SMALL-ANGLE SCATTERING;INOSINE MONOPHOSPHATE DEHYDROGENASE
KW  - IMP DEHYDROGENASE
KW  - CRYO-EM
KW  - MECHANISM
KW  - INHIBITORS
KW  - TOOLS
UR  - https://www.nature.com/articles/s41467-024-50933-6
N2  - 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.
ER  -

BULVAS, Ondrej; Zdenek KNEJZLIK; Jakub SYS; Anatolij FILIMONENKO; Monika CIZKOVA; Kamila CLAROVA; Dominik REJMAN; Tomas KOUBA a Iva PICHOVA. Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase. \textit{Nature Communications}. Berlin: Nature, 2024, roč.~15, č.~1, s.~1-14. ISSN~2041-1723. Dostupné z: https://doi.org/10.1038/s41467-024-50933-6.

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