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1.
Improved Glucose‐Neopentyl Glycol (GNG) Amphiphiles for Membrane Protein Solubilization and Stabilization 下载免费PDF全文
Kyung Ho Cho Hyoung Eun Bae Dr. Manabendra Das Prof. Samuel H. Gellman Prof. Pil Seok Chae 《化学:亚洲杂志》2014,9(2):632-638
Membrane proteins are inherently amphipathic and undergo dynamic conformational changes for proper function within native membranes. Maintaining the functional structures of these biomacromolecules in aqueous media is necessary for structural studies but difficult to achieve with currently available tools, thus necessitating the development of novel agents with favorable properties. This study introduces several new glucose‐neopentyl glycol (GNG) amphiphiles and reveals some agents that display favorable behaviors for the solubilization and stabilization of a large, multi‐subunit membrane protein assembly. Furthermore, a detergent structure–property relationship that could serve as a useful guideline for the design of novel amphiphiles is discussed. 相似文献
2.
Prof. Pil Seok Chae Prof. Søren G. F. Rasmussen Rohini R. Rana Kamil Gotfryd Andrew C. Kruse Aashish Manglik Kyung Ho Cho Shailika Nurva Prof. Ulrik Gether Prof. Lan Guan Prof. Claus J. Loland Dr. Bernadette Byrne Prof. Brian K. Kobilka Prof. Samuel H. Gellman 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(16):4964-4964
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Hydrophobic Variations of N‐Oxide Amphiphiles for Membrane Protein Manipulation: Importance of Non‐hydrocarbon Groups in the Hydrophobic Portion 下载免费PDF全文
Amphipathic agents called detergents serve as membrane‐mimetic systems to maintain the native structures of membrane proteins during their manipulation. However, membrane proteins solubilized in conventional detergents tend to undergo denaturation and aggregation, necessitating the development of novel amphipathic agents with enhanced properties. Here we describe several new amphiphiles that contain an N‐oxide group as the hydrophilic portion. The new amphiphiles have been evaluated for the ability to solubilize and stabilize a fragile multi‐subunit assembly from biological membranes. We found that cholate‐based agents were promising in supporting retention of the native protein quaternary structure, while deoxycholate‐based amphiphiles were highly efficient in extracting/solubilizing the intact superassembly from the native membrane. Monitoring superassembly solubilization and stabilization as a function of variation in amphiphile structure led us to propose that a non‐hydrocarbon moiety such as an amide, ether, or a hydroxy group present in the lipophilic regions can manifest distinctive effects in the context of membrane protein manipulation. 相似文献
4.
Prof. Pil Seok Chae Prof. Søren G. F. Rasmussen Rohini R. Rana Kamil Gotfryd Andrew C. Kruse Aashish Manglik Kyung Ho Cho Shailika Nurva Prof. Ulrik Gether Prof. Lan Guan Prof. Claus J. Loland Dr. Bernadette Byrne Prof. Brian K. Kobilka Prof. Samuel H. Gellman 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(31):9434-9434
5.
Kyung Ho Cho Dr. Yang Du Nicola J. Scull Dr. Parameswaran Hariharan Prof. Kamil Gotfryd Prof. Claus J. Loland Prof. Lan Guan Dr. Bernadette Byrne Prof. Brian K. Kobilka Prof. Pil Seok Chae 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(28):10008-10013
Membrane proteins are key functional players in biological systems. These biomacromolecules contain both hydrophilic and hydrophobic regions and thus amphipathic molecules are necessary to extract membrane proteins from their native lipid environments and stabilise them in aqueous solutions. Conventional detergents are commonly used for membrane protein manipulation, but membrane proteins surrounded by these agents often undergo denaturation and aggregation. In this study, a novel class of maltoside‐bearing amphiphiles, with a xylene linker in the central region, designated xylene‐linked maltoside amphiphiles (XMAs) was developed. When these novel agents were evaluated with a number of membrane proteins, it was found that XMA‐4 and XMA‐5 have particularly favourable efficacy with respect to membrane protein stabilisation, indicating that these agents hold significant potential for membrane protein structural study. 相似文献
6.
Hazrat Hussain Dr. Yang Du Nicola J. Scull Jonas S. Mortensen Jeffrey Tarrasch Hyoung Eun Bae Prof. Claus J. Loland Dr. Bernadette Byrne Prof. Brian K. Kobilka Prof. Pil Seok Chae 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(21):7068-7073
Integral membrane proteins are amphipathic molecules crucial for all cellular life. The structural study of these macromolecules starts with protein extraction from the native membranes, followed by purification and crystallisation. Detergents are essential tools for these processes, but detergent‐solubilised membrane proteins often denature and aggregate, resulting in loss of both structure and function. In this study, a novel class of agents, designated mannitol‐based amphiphiles (MNAs), were prepared and characterised for their ability to solubilise and stabilise membrane proteins. Some of MNAs conferred enhanced stability to four membrane proteins including a G protein‐coupled receptor (GPCR), the β2 adrenergic receptor (β2AR), compared to both n‐dodecyl‐d ‐maltoside (DDM) and the other MNAs. These agents were also better than DDM for electron microscopy analysis of the β2AR. The ease of preparation together with the enhanced membrane protein stabilisation efficacy demonstrates the value of these agents for future membrane protein research. 相似文献
7.
Dr. Lubna Ghani Dr. Seonghoon Kim Dr. Haoqing Wang Hyun Sung Lee Dr. Jonas S. Mortensen Dr. Satoshi Katsube Dr. Yang Du Dr. Aiman Sadaf Dr. Waqar Ahmed Prof. Bernadette Byrne Prof. Lan Guan Prof. Claus J. Loland Prof. Brian K. Kobilka Prof. Wonpil Im Prof. Pil Seok Chae 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(21):e202200116
Membrane proteins are of biological and pharmaceutical significance. However, their structural study is extremely challenging mainly due to the fact that only a small number of chemical tools are suitable for stabilizing membrane proteins in solution. Detergents are widely used in membrane protein study, but conventional detergents are generally poor at stabilizing challenging membrane proteins such as G protein-coupled receptors and protein complexes. In the current study, we prepared tandem triazine-based maltosides (TZMs) with two amphiphilic triazine units connected by different diamine linkers, hydrazine (TZM−Hs) and 1,2-ethylenediamine (TZM−Es). These TZMs were consistently superior to a gold standard detergent (DDM) in terms of stabilizing a few membrane proteins. In addition, the TZM−Es containing a long linker showed more general protein stabilization efficacy with multiple membrane proteins than the TZM−Hs containing a short linker. This result indicates that introduction of the flexible1,2-ethylenediamine linker between two rigid triazine rings enables the TZM−Es to fold into favourable conformations in order to promote membrane protein stability. The novel concept of detergent foldability introduced in the current study has potential in rational detergent design and membrane protein applications. 相似文献
8.
Kyung Ho Cho Orquidea Ribeiro Dr. Yang Du Dr. Elena Tikhonova Jonas S. Mortensen Kelsey Markham Dr. Parameswaran Hariharan Prof. Claus J. Loland Prof. Lan Guan Prof. Brian K. Kobilka Dr. Bernadette Byrne Prof. Pil Seok Chae 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(52):18833-18839
Detergents serve as useful tools for membrane protein structural and functional studies. Their amphipathic nature allows detergents to associate with the hydrophobic regions of membrane proteins whilst maintaining the proteins in aqueous solution. However, widely used conventional detergents are limited in their ability to maintain the structural integrity of membrane proteins and thus there are major efforts underway to develop novel agents with improved properties. We prepared mesitylene‐cored glucoside amphiphiles (MGAs) with three alkyl chains and compared these agents with previously developed xylene‐linked maltoside agents (XMAs) with two alkyl chains and a conventional detergent (DDM). When these agents were evaluated for four membrane proteins including a G protein‐coupled receptor (GPCR), some agents such as MGA‐C13 and MGA‐C14 resulted in markedly enhanced stability of membrane proteins compared to both DDM and the XMAs. This favourable behaviour is due likely to the increased hydrophobic density provided by the extra alkyl chain. Thus, this study not only describes new glucoside agents with potential for membrane protein research, but also introduces a new detergent design principle for future development. 相似文献
9.
Muhammad Ehsan Ashwani Kumar Jonas S. Mortensen Yang Du Parameswaran Hariharan Kaavya K. Kumar Betty Ha Bernadette Byrne Lan Guan Brian K. Kobilka Claus J. Loland Pil Seok Chae 《化学:亚洲杂志》2019,14(11):1926-1931
We prepared an amphiphile with a penta‐phenylene lipophilic group and a branched trimaltoside head group. This new agent, designated penta‐phenylene maltoside (PPM), showed a marked tendency to self‐assembly into micelles via strong aromatic–aromatic interactions in aqueous media, as evidenced by 1H NMR spectroscopy and fluorescence studies. When utilized for membrane protein studies, this new agent was superior to DDM, a gold standard conventional detergent, in stabilizing multiple proteins long term. The ability of this agent to form aromatic–aromatic interactions is likely responsible for enhanced protein stabilization when associated with a target membrane protein. 相似文献
10.
Glycosyl‐Substituted Dicarboxylates as Detergents for the Extraction,Overstabilization, and Crystallization of Membrane Proteins 下载免费PDF全文
Dr. Kim‐Anh Nguyen Dr. Marine Peuchmaur Sandrine Magnard Dr. Romain Haudecoeur Dr. Cédric Boyère Saravanan Mounien Ikram Benammar Veronica Zampieri Dr. Sébastien Igonet Dr. Vincent Chaptal Dr. Anass Jawhari Prof. Ahcène Boumendjel Dr. Pierre Falson 《Angewandte Chemie (International ed. in English)》2018,57(11):2948-2952
To tackle the problems associated with membrane protein (MP) instability in detergent solutions, we designed a series of glycosyl‐substituted dicarboxylate detergents (DCODs) in which we optimized the polar head to clamp the membrane domain by including, on one side, two carboxyl groups that form salt bridges with basic residues abundant at the membrane–cytoplasm interface of MPs and, on the other side, a sugar to form hydrogen bonds. Upon extraction, the DCODs 8 b , 8 c , and 9 b preserved the ATPase function of BmrA, an ATP‐binding cassette pump, much more efficiently than reference or recently designed detergents. The DCODs 8 a , 8 b , 8 f , 9 a , and 9 b induced thermal shifts of 20 to 29 °C for BmrA and of 13 to 21 °C for the native version of the G‐protein‐coupled adenosine receptor A2AR. Compounds 8 f and 8 g improved the diffraction resolution of BmrA crystals from 6 to 4 Å. DCODs are therefore considered to be promising and powerful tools for the structural biology of MPs. 相似文献
11.
Mark Damen Mario A. Izidoro Debora N. Okamoto Lilian C. G. Oliveira Helene I. V. Amatdjais-Groenen Stijn F. M. van Dongen Koen W. R. van Cleef Ronald P. van Rij Cindy E. J. Dieteren Daniel Girons Bernd N. M. van Buuren Byron E. E. Martina Albert D. M. E. Osterhaus Luiz Juliano Bob J. Scholte Martin C. Feiters 《Molecules (Basel, Switzerland)》2022,27(10)
Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C15H31C(O)-Lys-(Gly or Ala)nLys-NHC16H33, shorthand notation C16-KXnK-C16 with X = A or G, and n = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC50 values in the lower µM range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue. 相似文献
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Tanya Lasitza-Male Kim Bartels Jakub Jungwirth Felix Wiggers Dr. Gabriel Rosenblum Dr. Hagen Hofmann Dr. Christian Löw 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(43):19283-19290
Membrane proteins require lipid bilayers for function. While lipid compositions reach enormous complexities, high-resolution structures are usually obtained in artificial detergents. To understand whether and how lipids guide membrane protein function, we use single-molecule FRET to probe the dynamics of DtpA, a member of the proton-coupled oligopeptide transporter (POT) family, in various lipid environments. We show that detergents trap DtpA in a dynamic ensemble with cytoplasmic opening. Only reconstitutions in more native environments restore cooperativity, allowing an opening to the extracellular side and a sampling of all relevant states. Bilayer compositions tune the abundance of these states. A novel state with an extreme cytoplasmic opening is accessible in bilayers with anionic head groups. Hence, chemical diversity of membranes translates into structural diversity, with the current POT structures only sampling a portion of the full structural space. 相似文献
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Dr. Muhammad Ehsan Dr. Yang Du Jonas S. Mortensen Dr. Parameswaran Hariharan Qianhui Qu Lubna Ghani Dr. Manabendra Das Anne Grethen Prof. Bernadette Byrne Prof. Georgios Skiniotis Prof. Sandro Keller Prof. Claus J. Loland Prof. Lan Guan Prof. Brian K. Kobilka Prof. Pil Seok Chae 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(49):11545-11554
Amphipathic agents are widely used in various fields including biomedical sciences. Micelle-forming detergents are particularly useful for in vitro membrane-protein characterization. As many conventional detergents are limited in their ability to stabilize membrane proteins, it is necessary to develop novel detergents to facilitate membrane-protein research. In the current study, we developed novel trimaltoside detergents with an alkyl pendant-bearing terphenyl unit as a hydrophobic group, designated terphenyl-cored maltosides (TPMs). We found that the geometry of the detergent hydrophobic group substantially impacts detergent self-assembly behavior, as well as detergent efficacy for membrane-protein stabilization. TPM-Vs, with a bent terphenyl group, were superior to the linear counterparts (TPM-Ls) at stabilizing multiple membrane proteins. The favorable protein stabilization efficacy of these bent TPMs is likely associated with a binding mode with membrane proteins distinct from conventional detergents and facial amphiphiles. When compared to n-dodecyl-β-d -maltoside (DDM), most TPMs were superior or comparable to this gold standard detergent at stabilizing membrane proteins. Notably, TPM-L3 was particularly effective at stabilizing the human β2 adrenergic receptor (β2AR), a G-protein coupled receptor, and its complex with Gs protein. Thus, the current study not only provides novel detergent tools that are useful for membrane-protein study, but also suggests a critical role for detergent hydrophobic group geometry in governing detergent efficacy. 相似文献
16.
《Angewandte Chemie (International ed. in English)》2017,56(1):380-383
Detergents are often used to investigate the structure and dynamics of membrane proteins. Whereas the structural integrity seems to be preserved in detergents for many membrane proteins, their functional activity is frequently compromised, but can be restored in a lipid environment. Herein we show with per‐residue resolution that while OmpX forms a stable β‐barrel in DPC detergent micelles, DHPC/DMPC bicelles, and DMPC nanodiscs, the pico‐ to nanosecond and micro‐ to millisecond motions differ substantially between the detergent and lipid environment. In particular for the β‐strands, there is pronounced dynamic variability in the lipid environment, which appears to be suppressed in micelles. This unexpected complex and membrane‐mimetic‐dependent dynamic behavior indicates that the frequent loss of membrane protein activity in detergents might be related to reduced internal dynamics and that membrane protein activity correlates with lipid flexibility. 相似文献
17.
Weiling Luo Meifang Yang Dr. Yitian Zhao Dr. Huixia Wang Prof. Xiaodi Yang Prof. Wei Zhang Prof. Fei Zhao Prof. Suwen Zhao Prof. Houchao Tao 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(69):e202202242
It is a pressing need, but still challenging to explore the structure and function of membrane proteins (MPs). One of the main obstacles is the limited availability of matched detergents for the handling of specific MPs. We describe herein the design of new detergents by incorporation of a transition linker between the hydrophilic head and the hydrophobic tail. This design allows a gradual change of hydrophobicity between the outside and inside of micelles, in contrast to the abrupt switch in conventional detergents. Notably, many of these detergents assembled into micelles in while retaining low critical micelle concentrations. Meanwhile, thermal stabilizing evaluation identified superior detergents for representative MPs, including G protein-coupled receptors and a transporter protein. Among them, further improved the NMR study of MPs. We anticipate these that results will encourage future detergent expansion through new remodeling on the traditional detergent scaffold. 相似文献
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Identification of Two Distinct Sites for Antagonist and Biased Agonist Binding to the Human Chemokine Receptor CXCR3 下载免费PDF全文
Lampros Milanos Noureldin Saleh Dr. Ralf C. Kling Jonas Kaindl Dr. Nuska Tschammer Prof. Dr. Timothy Clark 《Angewandte Chemie (International ed. in English)》2016,55(49):15277-15281
The chemokine receptor CXCR3 is a G protein‐coupled receptor that conveys extracellular signals into cells by changing its conformation upon ligand binding. We previously hypothesized that small‐molecule allosteric CXCR3‐agonists do not bind to the same allosteric binding pocket as 8‐azaquinazolinone‐based negative allosteric modulators. We have now performed molecular‐dynamics (MD) simulations with metadynamics enhanced sampling on the CXCR3 system to refine structures and binding modes and to predict the CXCR3‐binding affinities of the biased allosteric agonist FAUC1036 and the negative allosteric modulator RAMX3. We have identified two distinct binding sites; a “shallow” and a second “deeper” pocket to which the biased allosteric agonist FAUC1036 and negative allosteric modulator RAMX3 bind, respectively. 相似文献
20.
Introducing Chirality into Nonionic Dendritic Amphiphiles and Studying Their Supramolecular Assembly
Dr. Sumit Kumar Dr. Kai Ludwig Dr. Boris Schade Dr. Hans von Berlepsch Dr. Ilona Papp Dr. Rahul Tyagi Monika Gulia Prof. Dr. Rainer Haag Priv.‐Doz. Dr. Christoph Böttcher 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(16):5629-5636
Chiral head groups have been introduced into water‐soluble hydroxyl‐terminated nonionic amphiphiles and the impact of the head group stereochemistry on the supramolecular ultrastructures has been studied. Enantiomeric isomers were compared with the achiral meso form and the racemic mixture by means of cryogenic transmission electron microscopy and circular dichroism spectroscopy. Structurally, all amphiphiles are composed of the first‐generation hydrophilic polyglycerol head group coupled to a single hydrophobic hexadecyl chain through an amide linkage and diaromatic spacer. The enantiomers aggregate to form twisted ribbons with uniform handedness, whereas the meso stereoisomer and racemic mixture produce elongated assemblies, namely, tubules and platelets, but without a chiral ultrastructure. Simulations on the molecular packing geometries of the stereoisomers indicate different preferential assembly routes that explain the individual supramolecular aggregation behavior. 相似文献