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

Wen Zhu, Ashish Radadiya, Claudine Bisson, Sabine Wenzel, Brian E. Nordin, Francisco Martínez-Márquez, Tsuyoshi Imasaki, Svetlana E. Sedelnikova, Adriana Coricello, Patrick Baumann, Alexandria H. Berry, Tyzoon K. Nomanbhoy, John W. Kozarich, Yi Jin, David W. Rice, Yuichiro Takagi, Nigel G.J. Richards

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Article number345
JournalCommunications Biology
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity'. Together they form a unique fingerprint.

  • Cite this

    Zhu, W., Radadiya, A., Bisson, C., Wenzel, S., Nordin, B. E., Martínez-Márquez, F., Imasaki, T., Sedelnikova, S. E., Coricello, A., Baumann, P., Berry, A. H., Nomanbhoy, T. K., Kozarich, J. W., Jin, Y., Rice, D. W., Takagi, Y., & Richards, N. G. J. (2019). High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. Communications Biology, 2(1), [345]. https://doi.org/10.1038/s42003-019-0587-z