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

Author:

Zhu WenORCID,Radadiya AshishORCID,Bisson Claudine,Wenzel SabineORCID,Nordin Brian E.,Martínez-Márquez Francisco,Imasaki TsuyoshiORCID,Sedelnikova Svetlana E.,Coricello AdrianaORCID,Baumann PatrickORCID,Berry Alexandria H.,Nomanbhoy Tyzoon K.,Kozarich John W.ORCID,Jin YiORCID,Rice David W.ORCID,Takagi YuichiroORCID,Richards Nigel G. J.ORCID

Abstract

AbstractExpression 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 abona fidedrug 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.

Funder

RCUK | Biotechnology and Biological Sciences Research Council

U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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