Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer.
Allosteric Regulation
Animals
Cell Line, Tumor
Crystallography, X-Ray
Guanylate Kinases
/ chemistry
Humans
Kinetics
Lung Neoplasms
/ metabolism
Mice
Mutagenesis, Site-Directed
Nuclear Magnetic Resonance, Biomolecular
Protein Structure, Tertiary
RNA Interference
RNA, Small Interfering
Recombinant Proteins
/ biosynthesis
enzyme kinetics
enzyme mutation
guanylate kinase
hGMPK
lung cancer
non-synonymous single nucleotide variants (nsSNV)
nuclear magnetic resonance (NMR)
protein structure
solution structure
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
02 08 2019
02 08 2019
Historique:
received:
07
05
2019
revised:
12
06
2019
pubmed:
16
6
2019
medline:
17
3
2020
entrez:
16
6
2019
Statut:
ppublish
Résumé
Human guanylate kinase (hGMPK) is the only known enzyme responsible for cellular GDP production, making it essential for cellular viability and proliferation. Moreover, hGMPK has been assigned a critical role in metabolic activation of antiviral and antineoplastic nucleoside-analog prodrugs. Given that hGMPK is indispensable for producing the nucleotide building blocks of DNA, RNA, and cGMP and that cancer cells possess elevated GTP levels, it is surprising that a detailed structural and functional characterization of hGMPK is lacking. Here, we present the first high-resolution structure of hGMPK in the apo form, determined with NMR spectroscopy. The structure revealed that hGMPK consists of three distinct regions designated as the LID, GMP-binding (GMP-BD), and CORE domains and is in an open configuration that is nucleotide binding-competent. We also demonstrate that nonsynonymous single-nucleotide variants (nsSNVs) of the hGMPK CORE domain distant from the nucleotide-binding site of this domain modulate enzymatic activity without significantly affecting hGMPK's structure. Finally, we show that knocking down the
Identifiants
pubmed: 31201273
pii: S0021-9258(20)30232-5
doi: 10.1074/jbc.RA119.009251
pmc: PMC6682748
doi:
Substances chimiques
RNA, Small Interfering
0
Recombinant Proteins
0
Guanylate Kinases
EC 2.7.4.8
Banques de données
PDB
['6NUI', '1LVG', '1EX6', '1EX7']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11920-11933Informations de copyright
© 2019 Khan et al.
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