Molecular basis of human asparagine synthetase inhibitor specificity
Molecular basis of human asparagine synthetase inhibitor specificity
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DOI：
10.1101/428508
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发表时间：
2018-09
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影响因子：
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通讯作者：
Wen Zhu;Ashish Radadiya;C. Bisson;B. Nordin;Patrick Baumann;T. Imasaki;S. Wenzel;S. Sedelnikova;A. Berry;T. Nomanbhoy;J. Kozarich;Yi Jin;Y. Takagi;D. Rice;N. Richards
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文献类型：
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作者：
Wen Zhu;Ashish Radadiya;C. Bisson;B. Nordin;Patrick Baumann;T. Imasaki;S. Wenzel;S. Sedelnikova;A. Berry;T. Nomanbhoy;J. Kozarich;Yi Jin;Y. Takagi;D. Rice;N. Richards
人天冬酰胺合成酶（ASNS）的表达促进了乳腺癌的转移进展，这影响了L-天冬酰胺水平和肿瘤细胞的侵袭性。因此，人ASNS已成为癌症治疗的真正药物靶标。我们已经报道了一种具有纳摩尔亲和力的缓慢起效、紧密结合的ASNS抑制剂，但我们的化合物表现出较差的细胞渗透性。另一方面，我们在这里表明，这种抑制剂表现出显着的选择性HCT-116细胞裂解物中的人ASNS。通过确定人类ASNS的第一个高分辨率（1.85 μ m）X射线晶体结构，我们建立了与我们的抑制剂复合的酶的计算模型，这为介导特异性的分子间相互作用提供了第一个见解。这些发现将促进第二代ASNS抑制剂的开发，从而发现预防转移的药物。
Expression of the enzyme human asparagine synthetase (ASNS) promotes metastatic progression in breast cancer, which affects L-asparagine levels and tumor cell invasiveness. Human ASNS has therefore emerged as a bona fide drug target for cancer therapy. We have reported a slow-onset, tight binding ASNS inhibitor with nanomolar affinity, but our compound exhibits poor cell permeability. On the other hand, we show here that this inhibitor exhibits remarkable selectivity for the human ASNS in HCT-116 cell lysates. By determining the first high-resolution (1.85 Å) X-ray crystal structure for human ASNS, we have built a computational model of the enzyme complexed to our inhibitor, which provides the first insights into the intermolecular interactions mediating specificity. These findings should facilitate the development of a second generation of ASNS inhibitors, leading to the discovery of drugs to prevent metastasis.