8UK6

Candida albicans glutaminyl tRNA synthetase (GLN4) in complex with N-pyrimidinyl-beta-thiophenylacrylamide

Summary for 8UK6

• Entry DOI: 10.2210/pdb8uk6/pdb
• Descriptor: glutamine--tRNA ligase, ZINC ION, (2E)-N-(pyrimidin-2-yl)-3-(thiophen-2-yl)prop-2-enamide, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, allosteric, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Candida albicans
• Total number of polymer chains: 1
• Total formula weight: 93783.95

Authors

Sychantha, D.,Wright, G.D. (deposition date: 2023-10-12, release date: 2024-03-06, Last modification date: 2024-05-01)

Primary citation

Puumala, E.,Sychantha, D.,Lach, E.,Reeves, S.,Nabeela, S.,Fogal, M.,Nigam, A.,Johnson, J.W.,Aspuru-Guzik, A.,Shapiro, R.S.,Uppuluri, P.,Kalyaanamoorthy, S.,Magolan, J.,Whitesell, L.,Robbins, N.,Wright, G.D.,Cowen, L.E.
Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-beta-thiophenylacrylamides exerts highly selective antifungal activity.
Cell Chem Biol, 31:760-, 2024

PubMed Abstract: Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth. NP-BTA was hypothesized to target C. albicans glutaminyl-tRNA synthetase, Gln4. Here, we confirmed through in vitro amino-acylation assays NP-BTA is a potent inhibitor of Gln4, and we defined how NP-BTA arrests Gln4's transferase activity using co-crystallography. This analysis also uncovered Met496 as a critical residue for the compound's species-selective target engagement and potency. Structure-activity relationship (SAR) studies demonstrated the NP-BTA scaffold is subject to oxidative and non-oxidative metabolism, making it unsuitable for systemic administration. In a mouse dermatomycosis model, however, topical application of the compound provided significant therapeutic benefit. This work expands the repertoire of antifungal protein synthesis target mechanisms and provides a path to develop Gln4 inhibitors.

PubMed: 38402621
DOI: 10.1016/j.chembiol.2024.01.010

Experimental method

X-RAY DIFFRACTION (2.73 Å)