Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
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嘌呤核苷酸抑制人解偶联蛋白1的结构基础。
DOI：
10.1126/sciadv.adh4251
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发表时间：
2023-06-02
期刊：
影响因子：
13.6
通讯作者：
Kunji, Edmund R. S.
中科院分区：
文献类型：
--
作者：
Jones, Scott A.;Gogoi, Prerana;Ruprecht, Jonathan J.;King, Martin S.;Lee, Yang;Zogg, Thomas;Pardon, Els;Chand, Deepak;Steimle, Stefan;Copeman, Danielle M.;Cotrim, Camila A.;Steyaert, Jan;Crichton, Paul G.;Moiseenkova-Bell, Vera;Kunji, Edmund R. S.
线粒体解偶联蛋白1（UCP1）赋予哺乳动物褐色脂肪组织以燃烧卡路里作为热量进行体温调节的特殊能力。当被脂肪酸激活时，UCP1催化质子穿过线粒体内膜的泄漏，使线粒体短路产生热量，绕过ATP合成。相比之下，嘌呤核苷酸结合并抑制UCP1，通过尚不清楚的分子机制调节质子泄漏。我们提出了冷冻电子显微镜结构的GTP抑制状态的UCP1，这是一致的，其非导电状态。嘌呤核苷酸通过广泛的相互作用网络交联UCP 1的跨膜螺旋。我们的研究结果提供了一个结构基础，了解的特异性和pH依赖性的调节机制。UCP1保留了线粒体载体样转运机制所需的所有关键功能和结构特征。分析表明，抑制剂结合阻止了UCP1用于促进质子泄漏的构象变化。嘌呤核苷酸抑制解偶联蛋白1在质子不可渗透的中间状态的pH依赖性机制。
Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo–electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier–like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak. Purine nucleotides inhibit uncoupling protein 1 in a proton-impermeable intermediary state by a pH-dependent mechanism.
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影响因子：
8.1
作者：
Cavalieri, Riccardo;Hazebroek, Marlou Klein;Cotrim, Camila A.;Lee, Yang;Kunji, Edmund R. S.;Jastroch, Martin;Keipert, Susanne;Crichton, Paul G.
通讯作者：
Crichton, Paul G.
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
64.5
作者：
Fedorenko A;Lishko PV;Kirichok Y
通讯作者：
Kirichok Y
影响因子：
2.9
作者：
Echtay, KS;Winkler, E;Klingenberg, M
通讯作者：
Klingenberg, M
DOI：
10.1016/j.bbabio.2015.09.013
发表时间：
2016-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
King MS;Kerr M;Crichton PG;Springett R;Kunji ERS
通讯作者：
Kunji ERS