6NUI

Human Guanylate Kinase

Summary for 6NUI

• Entry DOI: 10.2210/pdb6nui/pdb
• NMR Information: BMRB: 27151
• Descriptor: Guanylate kinase (1 entity in total)
• Functional Keywords: purine metabolism, atp:gmp-phosphotransferase, gmp kinase, unliganded, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 21891.73

Authors

Sabo, T.M.,Khan, N.,Ban, D.,Trigo-Mourino, P.,Carneiro, M.G.,Trent, J.O.,Konrad, M.,Lee, D. (deposition date: 2019-02-01, release date: 2019-06-26, Last modification date: 2026-02-11)

Primary citation

Khan, N.,Shah, P.P.,Ban, D.,Trigo-Mourino, P.,Carneiro, M.G.,DeLeeuw, L.,Dean, W.L.,Trent, J.O.,Beverly, L.J.,Konrad, M.,Lee, D.,Sabo, T.M.
Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer.
J.Biol.Chem., 294:11920-11933, 2019

PubMed Abstract: 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 gene in lung adenocarcinoma cell lines decreases cellular viability, proliferation, and clonogenic potential while not altering the proliferation of immortalized, noncancerous human peripheral airway cells. Taken together, our results provide an important step toward establishing hGMPK as a potential biomolecular target, from both an orthosteric (ligand-binding sites) and allosteric (location of CORE domain-located nsSNVs) standpoint.

PubMed: 31201273
DOI: 10.1074/jbc.RA119.009251

Experimental method

SOLUTION NMR