Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.
Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.
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DOI：
10.1042/bcj20210647
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发表时间：
2021-12-10
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鸟氨酸脱羧酶（ODC）是多胺合成的限速酶。PA是增殖所需的肿瘤抑制剂，药物ODC抑制剂用于治疗过度增殖性疾病，包括癌症和感染性疾病。最有效的ODC抑制剂是1-氨基-氧-3-氨基丙烷（阿帕）。先前ODC-APA复合物的晶体结构表明阿帕非共价结合ODC及其辅因子吡哆醛5-磷酸（PLP），并通过与ODC底物鸟氨酸竞争结合到催化位点来发挥作用。我们通过APA结合ODC的新晶体结构重新审视了阿帕结合和ODC抑制的机制，我们在2.49 nm分辨率下解决了该问题。该结构明确显示阿帕和PLP在催化位点之间存在共价肟，我们在溶液中通过质谱法证实了这一点。稳定的肟与ODC发生广泛的相互作用，但不能被分解代谢，这解释了阿帕在ODC抑制中的高效力。此外，我们解决了ODC/PLP复合物结构与柠檬酸盐结合在底物结合口袋。这两种结构为开发更有效的药物ODC抑制剂提供了新的结构支架。
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC–APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 Å resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA’s high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors.
影响因子：
2.7
作者：
Klee, Nina;Wong, Pui Ee;Baragana, Beatriz;El Mazouni, Farah;Phillips, Margaret A.;Barrett, Michael P.;Gilbert, Ian H.
通讯作者：
Gilbert, Ian H.