High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity

Zhu, Wen, Radadiya, Ashish ORCID: https://orcid.org/0000-0001-7348-1755, Bisson, Claudine, Wenzel, Sabine, Nordin, Brian E., Martínez-Márquez, Francisco, Imasaki, Tsuyoshi, Sedelnikova, Svetlana E., Coricello, Adriana, Baumann, Patrick, Berry, Alexandria H., Nomanbhoy, Tyzoon K., Kozarich, John W., Jin, Yi ORCID: https://orcid.org/0000-0002-6927-4371, Rice, David W., Takagi, Yuichiro and Richards, Nigel G. J. ORCID: https://orcid.org/0000-0002-0375-0881 2019. High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. Communications Biology 2 , 345. 10.1038/s42003-019-0587-z

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Abstract

Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a bona fide drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 μM concentration in HCT-116 cell lysates with almost no off-target binding. The high-resolution (1.85 Å) crystal structure of human ASNS has enabled us to identify a cluster of negatively charged side chains in the synthetase domain that plays a key role in inhibitor binding. Comparing this structure with those of evolutionarily related AMP-forming enzymes provides insights into intermolecular interactions that give rise to the observed binding selectivity. Our findings demonstrate the feasibility of developing second generation human ASNS inhibitors as lead compounds for the discovery of drugs against metastasis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Chemistry
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher:	Nature Research
ISSN:	2399-3642
Date of First Compliant Deposit:	26 September 2019
Date of Acceptance:	21 August 2019
Last Modified:	06 Jan 2024 02:24
URI:	https://orca.cardiff.ac.uk/id/eprint/125637

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