Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Zhu, Wen, Radadiya, Ashish, 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, Rice, David W., Takagi, Yuichiro and Richards, Nigel G. J. 2019. High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. Communications Biology 2 (1) , 345. 10.1038/s42003-019-0587-z

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (2MB)

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: Chemistry
Publisher: Nature Research
ISSN: 2399-3642
Date of First Compliant Deposit: 26 September 2019
Date of Acceptance: 21 August 2019
Last Modified: 30 Nov 2019 06:52
URI: http://orca.cf.ac.uk/id/eprint/125637

Actions (repository staff only)

Edit Item Edit Item