TY - JOUR
T1 - High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity
AU - Zhu, Wen
AU - Radadiya, Ashish
AU - Bisson, Claudine
AU - Wenzel, Sabine
AU - Nordin, Brian E.
AU - Martínez-Márquez, Francisco
AU - Imasaki, Tsuyoshi
AU - Sedelnikova, Svetlana E.
AU - Coricello, Adriana
AU - Baumann, Patrick
AU - Berry, Alexandria H.
AU - Nomanbhoy, Tyzoon K.
AU - Kozarich, John W.
AU - Jin, Yi
AU - Rice, David W.
AU - Takagi, Yuichiro
AU - Richards, Nigel G. J.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1038/s42003-019-0587-z
DO - 10.1038/s42003-019-0587-z
M3 - Article
SN - 2399-3642
VL - 2
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 345 (2019)
ER -
