500kDa酵母乙-CoA碳酸酶全酶二元体的晶体结构
1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Nature
|October 13, 2015
概括
在Saccharomyces cerevisiae的晶体结构中,可以发现其独特的结构和催化机制. 这一发现为脂肪酸代谢和糖尿病和癌症等疾病的潜在药物标提供了洞察力.
科学领域:
- 生物化学
- 结构生物学
- 酵素学
背景情况:
- 乙-CoA碳酸酶 (ACC) 对脂肪酸代谢至关重要,也是治疗糖尿病和癌症的点.
- 糖菌 (Saccharomyces cerevisiae ACC) 在非常长链脂肪酸生产和核膜维护中起着关键作用.
- 虽然ACC和其他生物依碳酶的结构已知,但全酶结构仍然难以捉摸.
研究的目的:
- 为了确定Saccharomyces cerevisiae全长乙-CoA碳酶 (ScACC) 全酶二聚体的晶体结构.
- 阐明SCACC独特的催化机制和调节的结构基础.
- 了解针对ACC的药物发现的结构性影响.
主要方法:
- 射线晶体学
- 对ScACC的500kDa全酶二元结构的分析
- 与个别域和相关酶的结构进行比较
主要成果:
- 确定了500kDa的ScACC全酶二聚体的晶体结构,揭示了与其他依赖生物的碳酸酶不同的独特结构.
- 中部区域包含五个域,对于定位生物碳酸酶 (BC) 和碳酸转移酶 (CT) 催化域至关重要.
- 在全酶中,BC域作为二聚体存在,与其单聚体形式分离不同,单独解释其催化不活性并揭示抑制机制.
结论:
- 确定的ScACC全酶结构为真核细胞的ACC功能提供了前所未有的洞察力.
- 结构发现解释了单独的BC域的催化不活性,并阐明了由索拉A和酸化抑制ACC的机制.
- 这项工作为针对各种疾病的结构性药物设计奠定了基础.
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