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哺乳动物TSPO的A147T多态性的结构完整性

Structural Integrity of the A147T Polymorph of Mammalian TSPO.

作者信息

Jaremko Mariusz, Jaremko Łukasz, Giller Karin, Becker Stefan, Zweckstetter Markus

机构信息

Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany).

German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen (Germany).

出版信息

Chembiochem. 2015 Jul 6;16(10):1483-9. doi: 10.1002/cbic.201500217. Epub 2015 Jun 10.

DOI:10.1002/cbic.201500217
PMID:25974690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5653209/
Abstract

Ligands of the transmembrane protein TSPO are used for imaging of brain inflammation, but a common polymorphism in TSPO complicates their application to humans. Here we determined the three-dimensional structure and side-chain dynamics of the A147T polymorph of mammalian TSPO in complex with the first-generation ligand PK11195. We show that A147T TSPO is able to retain the same structural and dynamic profile as the wild-type protein and thus binds PK11195 with comparable affinity. Our study is important for the design of more potent diagnostic and therapeutic ligands of TSPO.

摘要

跨膜蛋白TSPO的配体用于脑部炎症成像，但TSPO中一种常见的多态性使其在人类中的应用变得复杂。在这里，我们确定了与第一代配体PK11195结合的哺乳动物TSPO的A147T多态性的三维结构和侧链动力学。我们表明，A147T TSPO能够保留与野生型蛋白相同的结构和动力学特征，因此以相当的亲和力结合PK11195。我们的研究对于设计更有效的TSPO诊断和治疗配体具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/ff1db35662e7/emss-74556-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/041f3f4f40f7/emss-74556-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/ac9856c34b9b/emss-74556-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/3a448ced88bd/emss-74556-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/586998d64300/emss-74556-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/ff1db35662e7/emss-74556-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/041f3f4f40f7/emss-74556-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/ac9856c34b9b/emss-74556-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/3a448ced88bd/emss-74556-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/586998d64300/emss-74556-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad9/5653209/ff1db35662e7/emss-74556-f005.jpg

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本文引用的文献

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Protein structure. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism.蛋白质结构。转运蛋白（TSPO）的晶体结构及人类多态性的突变模拟物。
Science. 2015 Jan 30;347(6221):555-8. doi: 10.1126/science.1260590.
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Protein structure. Structure and activity of tryptophan-rich TSPO proteins.蛋白质结构。富含色氨酸的TSPO蛋白的结构与活性。
Science. 2015 Jan 30;347(6221):551-5. doi: 10.1126/science.aaa1534.
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Positron emission tomography and functional characterization of a complete PBR/TSPO knockout.正电子发射断层扫描及完全型外周型苯二氮䓬受体/转位蛋白基因敲除的功能特性分析
新型 TSPO 突变体和血红素结合体的晶体结构，其柔性、配体结合和卟啉降解活性发生改变。
Biochemistry. 2023 Apr 4;62(7):1262-1273. doi: 10.1021/acs.biochem.2c00612. Epub 2023 Mar 22.
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Differential mitochondrial protein interaction profile between human translocator protein and its A147T polymorphism variant.人源转位蛋白及其 A147T 多态性变体的线粒体蛋白相互作用谱的差异。
PLoS One. 2022 May 6;17(5):e0254296. doi: 10.1371/journal.pone.0254296. eCollection 2022.
5
Radiosynthesis and characterization of [F]BS224: a next-generation TSPO PET ligand insensitive to the rs6971 polymorphism.[F]BS224 的放射性合成与表征：一种对 rs6971 多态性不敏感的新一代 TSPO PET 配体。
Eur J Nucl Med Mol Imaging. 2021 Dec;49(1):110-124. doi: 10.1007/s00259-021-05617-4. Epub 2021 Nov 16.
6
TSPO protein binding partners in bacteria, animals, and plants.TSPO 蛋白在细菌、动物和植物中的结合伴侣。
J Bioenerg Biomembr. 2021 Aug;53(4):463-487. doi: 10.1007/s10863-021-09905-4. Epub 2021 Jun 30.
7
The Interplay of Cholesterol and Ligand Binding in TSPO from Classical Molecular Dynamics Simulations.基于经典分子动力学模拟的TSPO中胆固醇与配体结合的相互作用
Molecules. 2021 Feb 26;26(5):1250. doi: 10.3390/molecules26051250.
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Membrane-embedded TSPO: an NMR view.膜结合 TSPO：NMR 的视角。
Eur Biophys J. 2021 Mar;50(2):173-180. doi: 10.1007/s00249-020-01487-0. Epub 2020 Dec 22.
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