A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins.
A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins.
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DOI：
10.1002/chem.201200069
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发表时间：
2012-07-27
影响因子：
4.3
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Chae, Pil Seok;Rasmussen, Soren G. F.;Rana, Rohini R.;Gotfryd, Kamil;Kruse, Andrew C.;Manglik, Aashish;Cho, Kyung Ho;Nurva, Shailika;Gether, Ulrik;Guan, Lan;Loland, Claus J.;Byrne, Bernadette;Kobilka, Brian K.;Gellman, Samuel H.
整合膜蛋白（IMP）是重要的细胞组分，介导环境和细胞质之间或不同细胞区室之间的物质和信号转移。IMP的结构和功能分析很重要;目前超过一半的药物靶向这类蛋白质。[1]IMP表征通常具有挑战性，有时甚至是不可能的，因为处理这些大分子存在困难。[2]天然状态的IMP显示大的疏水表面，其与水性环境不相容;因此，需要洗涤剂从脂质双层中提取IMP并保持溶液中蛋白质的天然状态。[3]对于这些应用，非离子洗涤剂，例如十二烷基-β-d-麦芽糖苷（DDM）和辛基-β-d-葡糖苷（OG）通常是优选的。尽管DDM、OG和相关去污剂的性质相对温和，但许多膜蛋白在用这些试剂溶解时变性和/或聚集。[4]已经追求不同的策略来开发用于从膜溶解IMP和用于在水溶液中维持这些蛋白质在天然样状态的新工具。对于增溶有效的技术并不总是稳定化的最佳技术，反之亦然。这些努力包括探索不同于传统洗涤剂结构的新型两亲分子。[5]特别值得注意的是促进IMP结晶的专门定制的两亲物。[5l两亲性聚合物（“amphipols”）[7]和通过两亲性蛋白质支架稳定的盘状脂质双层（“纳米盘”）[8]代表了用于在水溶液中稳定天然样状态的IMP的高度创新的方法。然而，目前尚不清楚这些方法是否可以支持高质量晶体的衍射分析生长。此外，无论是Amphipol还是nanodisks都没有被设计用于从生物膜中提取IMP。尽管在开发膜蛋白增溶和稳定的新化合物和策略方面取得了相当大的进展，但仍需要新的工具，因为许多IMP目前是难治的。鉴于膜蛋白之间的结构和物理性质的巨大变化，单一的两亲物或两亲物家族对于每个系统或甚至大多数系统都是最佳的，因此探索新的两亲性试剂对于膜蛋白生物化学是重要的。在这里，我们报告了一类结构新颖的两亲物，显示良好的行为，相对于传统的洗涤剂，如DDM，对一组不同的膜蛋白。
Integral membrane proteins (IMPs) are crucial cellular components, mediating the transfer of material and signals between the environment and the cytoplasm, or between different cellular compartments. Structural and functional analysis of IMPs is important; more than half of current pharmaceutical agents target proteins in this class.[1] IMP characterization is often challenging, and sometimes impossible, because of difficulties associated with handling these macromolecules.[2] IMPs in the native state display large hydrophobic surfaces, which are not compatible with an aqueous environment; therefore, detergents are required to extract IMPs from the lipid bilayer and to maintain the native state of the protein in solution.[3] Nonionic detergents, such as dodecyl-β-d-maltoside (DDM) and octyl-β-d-glucoside (OG), are generally preferred for these applications. Despite the comparatively mild nature of DDM, OG and related detergents, many membrane proteins denature and/or aggregate upon solubilization with these agents.[4] Diverse strategies have been pursued to develop new tools for solubilization of IMPs from membranes and for maintenance of these proteins in a native-like state in aqueous solution. Techniques that are effective for solubilization are not always optimal for stabilization, and vice versa. These efforts have included exploration of novel amphiphilic molecules that depart from traditional detergent architectures.[5] Specifically tailored amphiphiles that facilitate IMP crystallization are particularly noteworthy.[5l, m, 6] Amphiphilic polymers (“amphipols”)[7] and discoidal lipid bilayers stabilized by an amphiphilic protein scaffold (“nanodiscs”)[8] represent highly innovative approaches for stabilizing IMPs in native-like states in aqueous solution. It is not clear, however, whether these approaches can support growth of highquality crystals for diffraction analysis. Furthermore, neither amphipols nor nanodiscs were designed to extract IMPs from biological membranes. Despite considerable progress in the development of new compounds and strategies for membrane protein solubilization and stabilization, new tools are needed, because many IMPs are currently refractory. Given the great variation in structure and physical properties among membrane proteins, it is very unlikely that a single amphiphile or amphiphile family will be optimal for every system, or even most systems, and exploration of new amphiphilic agents is therefore important for membrane protein biochemistry. Herein we report a class of structurally novel amphiphiles that display favorable behavior, relative to traditional detergents such as DDM, toward a diverse set of membrane proteins.
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影响因子：
2.9
作者：
Howell, Stanley C.;Mittal, Ritesh;Sanders, Charles R.
通讯作者：
Sanders, Charles R.
影响因子：
6.2
作者：
Bazzacco, Paola;Sharma, K. Shivaji;Pucci, Bernard
通讯作者：
Pucci, Bernard
用于膜蛋白稳定的串联面两亲物。
影响因子：
15
作者：
Chae PS;Gotfryd K;Pacyna J;Miercke LJ;Rasmussen SG;Robbins RA;Rana RR;Loland CJ;Kobilka B;Stroud R;Byrne B;Gether U;Gellman SH
通讯作者：
Gellman SH
影响因子：
15
作者：
Chae, Pil Seok;Guzei, Ilia A.;Gellman, Samuel H.
通讯作者：
Gellman, Samuel H.
影响因子：
5.7
作者：
Alexandrov, Alexander I.;Mileni, Mauro;Stevens, Raymond C.
通讯作者：
Stevens, Raymond C.