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

DOI: 10.1038/s42003-019-0587-z DOI Help

Authors: Wen Zhu (Cardiff University; University of California) , Ashish Radadiya (Cardiff University) , Claudine Bisson (University of Sheffield) , Sabine Wenzel (Indiana University School of Medicine) , Brian E. Nordin (ActivX Biosciences, Inc; Vividion Therapeutics) , Francisco Martínez-márquez (Indiana University School of Medicine) , Tsuyoshi Imasaki (Indiana University School of Medicine; Kobe University Graduate School of Medicine) , Svetlana E. Sedelnikova (University of Sheffield) , Adriana Coricello (Cardiff University) , Patrick Baumann (Cardiff University) , Alexandria H. Berry (California Institute of Technology) , Tyzoon K. Nomanbhoy (ActivX Biosciences, Inc) , John W. Kozarich (ActivX Biosciences, Inc) , Yi Jin (Cardiff University) , David W. Rice (University of Sheffield) , Yuichiro Takagi (Indiana University School of Medicine) , Nigel G. J. Richards (Cardiff University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Communications Biology , VOL 2

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 12788

Open Access Open Access

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.

Journal Keywords: Computational models; Enzymes; Medicinal chemistry; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Documents:
s42003-019-0587-z.pdf