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Das, M.,Du, Y.,Mortensen, J.,Ribeiro, O.,Hariharan, P.,Guan, L.,Loland, C.,Kobilka, B.,Byrne, B.,Chae, P. THE ROYAL SOCIETY OF CHEMISTRY 2017 Chemical Science Vol.8 No.2
<P>Amphiphile selection is a crucial step in membrane protein structural and functional study. As conventional detergents have limited scope and utility, novel agents with enhanced efficacy need to be developed. Although a large number of novel agents have been reported, so far there has been no systematically designed comparative study of the protein stabilization efficacy of stereo-isomeric amphiphiles. Here we designed and prepared a novel class of stereo-isomeric amphiphiles, designated butane-1,2,3,4-tetraolbased maltosides (BTMs). These stereoisomers showed markedly different behaviour for most of the targeted membrane proteins depending on the chirality of the linker region. These findings indicate an important role for detergent stereochemistry in membrane protein stabilization. In addition, we generally observed enhanced detergent efficacy with increasing alkyl chain length, reinforcing the importance of the balance between hydrophobicity and hydrophilicity in detergent design. The stereo-isomeric difference in detergent efficacy observed provides an important design principle for the development of novel amphiphiles for membrane protein manipulation.</P>
A class of rigid linker-bearing glucosides for membrane protein structural study
Sadaf, A.,Mortensen, J.,Capaldi, S.,Tikhonova, E.,Hariharan, P.,Ribeiro, O.,Loland, C.,Guan, L.,Byrne, B.,Chae, P. THE ROYAL SOCIETY OF CHEMISTRY 2016 Chemical Science Vol.7 No.3
<P>Membrane proteins are amphipathic bio-macromolecules incompatible with the polar environments of aqueous media. Conventional detergents encapsulate the hydrophobic surfaces of membrane proteins allowing them to exist in aqueous solution. Membrane proteins stabilized by detergent micelles are used for structural and functional analysis. Despite the availability of a large number of detergents, only a few agents are sufficiently effective at maintaining the integrity of membrane proteins to allow successful crystallization. In the present study, we describe a novel class of synthetic amphiphiles with a branched tail group and a triglucoside head group. These head and tail groups were connected via an amide or ether linkage by using a tris(hydroxylmethyl) aminomethane (TRIS) or neopentyl glycol (NPG) linker to produce TRIS-derived triglucosides (TDTs) and NPG-derived triglucosides (NDTs), respectively. Members of this class conferred enhanced stability on target membrane proteins compared to conventional detergents. Because of straightforward synthesis of the novel agents and their favourable effects on a range of membrane proteins, these agents should be of wide applicability to membrane protein science.</P>
New penta-saccharide-bearing tripod amphiphiles for membrane protein structure studies
Ehsan, Muhammad,Ghani, Lubna,Du, Yang,Hariharan, Parameswaran,Mortensen, Jonas S.,Ribeiro, Orquidea,Hu, Hongli,Skiniotis, Georgios,Loland, Claus J.,Guan, Lan,Kobilka, Brian K.,Byrne, Bernadette,Chae, Royal Society of Chemistry 2017 The Analyst Vol.142 No.20
<P>Integral membrane proteins either alone or as complexes carry out a range of key cellular functions. Detergents are indispensable tools in the isolation of membrane proteins from biological membranes for downstream studies. Although a large number of techniques and tools, including a wide variety of detergents, are available, purification and structural characterization of many membrane proteins remain challenging. In the current study, a new class of tripod amphiphiles bearing two different penta-saccharide head groups, designated TPSs, were developed and evaluated for their ability to extract and stabilize a range of diverse membrane proteins. Variations in the structures of the detergent head and tail groups allowed us to prepare three sets of the novel agents with distinctive structures. Some TPSs (TPS-A8 and TPS-E7) were efficient at extracting two proteins in a functional state while others (TPS-E8 and TPS-E10L) conferred marked stability to all membrane proteins (and membrane protein complexes) tested here compared to a conventional detergent. Use of TPS-E10L led to clear visualization of a receptor-Gs complex using electron microscopy, indicating profound potential in membrane protein research.</P>
Dendronic trimaltoside amphiphiles (DTMs) for membrane protein study
Sadaf, Aiman,Du, Yang,Santillan, Claudia,Mortensen, Jonas S.,Molist, Iago,Seven, Alpay B.,Hariharan, Parameswaran,Skiniotis, Georgios,Loland, Claus J.,Kobilka, Brian K.,Guan, Lan,Byrne, Bernadette,Cha Royal Society of Chemistry 2017 Chemical Science Vol.8 No.12
<▼1><P>A novel amphiphile with a dendronic hydrophobic group (DTM-A6) was markedly effective at stabilizing and visualizing a GPCR-G<SUB>s</SUB> complex.</P></▼1><▼2><P>The critical contribution of membrane proteins in normal cellular function makes their detailed structure and functional analysis essential. Detergents, amphipathic agents with the ability to maintain membrane proteins in a soluble state in aqueous solution, have key roles in membrane protein manipulation. Structural and functional stability is a prerequisite for biophysical characterization. However, many conventional detergents are limited in their ability to stabilize membrane proteins, making development of novel detergents for membrane protein manipulation an important research area. The architecture of a detergent hydrophobic group, that directly interacts with the hydrophobic segment of membrane proteins, is a key factor in dictating their efficacy for both membrane protein solubilization and stabilization. In the current study, we developed two sets of maltoside-based detergents with four alkyl chains by introducing dendronic hydrophobic groups connected to a trimaltoside head group, designated dendronic trimaltosides (DTMs). Representative DTMs conferred enhanced stabilization to multiple membrane proteins compared to the benchmark conventional detergent, DDM. One DTM (<I>i.e.</I>, DTM-A6) clearly outperformed DDM in stabilizing human β<SUB>2</SUB> adrenergic receptor (β<SUB>2</SUB>AR) and its complex with G<SUB>s</SUB> protein. A further evaluation of this DTM led to a clear visualization of β<SUB>2</SUB>AR-G<SUB>s</SUB> complex <I>via</I> electron microscopic analysis. Thus, the current study not only provides novel detergent tools useful for membrane protein study, but also suggests that the dendronic architecture has a role in governing detergent efficacy for membrane protein stabilization.</P></▼2>
Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study
Cho, Kyung Ho,Husri, Mohd,Amin, Anowarul,Gotfryd, Kamil,Lee, Ho Jin,Go, Juyeon,Kim, Jin Woong,Loland, Claus J.,Guan, Lan,Byrne, Bernadette,Chae, Pil Seok The Royal Society of Chemistry 2015 The Analyst Vol.140 No.9
<P>Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, <I>n</I>-dodecyl-β-<SMALL>D</SMALL>-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation.</P> <P>Graphic Abstract</P><P>The hydrophobic variants of the original MNG (MNG-3-C10) were evaluated with a few membrane proteins. The optimal MNG was variable for different membrane proteins, indicative of importance of match/mismatch between detergent hydrophobicity and membrane protein propensity to aggregate and denature. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c5an00240k'> </P>
Das, Manabendra,Du, Yang,Ribeiro, Orquidea,Hariharan, Parameswaran,Mortensen, Jonas S.,Patra, Dhabaleswar,Skiniotis, Georgios,Loland, Claus J.,Guan, Lan,Kobilka, Brian K.,Byrne, Bernadette,Chae, Pil S American Chemical Society 2017 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.139 No.8
<P>Detergents are essential tools for functional and structural studies of membrane proteins. However, conventional detergents are limited in their scope and utility, particularly for eukaryotic membrane proteins. Thus, there are major efforts to develop new amphipathic agents with enhanced properties. Here, a novel class of diastereomeric agents with a preorganized conformation, designated norbornane-based maltosides (NBMs), were prepared and evaluated for their ability to solubilize and stabilize membrane proteins. Representative NBMs displayed enhanced behaviors compared to n-dodecyl-beta-D-maltoside (DDM) for all membrane proteins tested. Efficacy of the individual NBMs varied depending on the overall detergent shape and alkyl chain length. Specifically, NBMs with no kink in the lipophilic region conferred greater stability to the proteins than NBMs with a kink. In addition, long alkyl chain NBMs were generally better at stabilizing membrane proteins than short alkyl chain agents. Furthermore, use of one well-behaving NBM enabled us to attain a marked stabilization and clear visualization of a challenging membrane protein complex using electron microscopy. Thus, this study not only describes novel maltoside detergents with enhanced protein stabilizing properties but also suggests that overall detergent geometry has an important role in determining membrane protein stability. Notably, this is the first systematic study on the effect of detergent kinking on micellar properties and associated membrane protein stability.</P>
Tandem neopentyl glycol maltosides (TNMs) for membrane protein stabilisation
Bae, Hyoung Eun,Mortensen, Jonas S.,Ribeiro, Orquidea,Du, Yang,Ehsan, Muhammad,Kobilka, Brian K.,Loland, Claus J.,Byrne, Bernadette,Chae, Pil Seok The Royal Society of Chemistry 2016 Chemical communications Vol.52 No.81
<P>A novel class of detergents, designated tandem neopentyl glycol maltosides (TNMs), were evaluated with four target membrane proteins. The best detergent varied depending on the target, but TNM-C12L and TNM-C11S were notable for their ability to confer increased membrane protein stability compared to DDM. These agents have potential for use in membrane protein research.</P>
A comparative study of branched and linear mannitol-based amphiphiles on membrane protein stability
Hussain, Hazrat,Helton, Tyler,Du, Yang,Mortensen, Jonas S.,Hariharan, Parameswaran,Ehsan, Muhammad,Byrne, Bernadette,Loland, Claus J.,Kobilka, Brian K.,Guan, Lan,Chae, Pil Seok The Royal Society of Chemistry 2018 The Analyst Vol.143 No.23
<P>The study of membrane proteins is extremely challenging, mainly because of the incompatibility of the hydrophobic surfaces of membrane proteins with an aqueous medium. Detergents are essential agents used to maintain membrane protein stability in non-native environments. However, conventional detergents fail to stabilize the native structures of many membrane proteins. Development of new amphipathic agents with enhanced efficacy for membrane protein stabilization is necessary to address this important problem. We have designed and synthesized linear and branched mannitol-based amphiphiles (MNAs), and comparative studies showed that most of the branched MNAs had advantages over the linear agents in terms of membrane protein stability. In addition, a couple of the new MNAs displayed favorable behaviors compared to <I>n</I>-dodecyl-β-d-maltoside and the previously developed MNAs in maintaining the native protein structures, indicating potential utility of these new agents in membrane protein study.</P>
Vitamin E-based glycoside amphiphiles for membrane protein structural studies
Ehsan, Muhammad,Du, Yang,Molist, Iago,Seven, Alpay B.,Hariharan, Parameswaran,Mortensen, Jonas S.,Ghani, Lubna,Loland, Claus J.,Skiniotis, Georgios,Guan, Lan,Byrne, Bernadette,Kobilka, Brian K.,Chae, The Royal Society of Chemistry 2018 Organic & Biomolecular Chemistry Vol.16 No.14
<P>Membrane proteins play critical roles in a variety of cellular processes. For a detailed molecular level understanding of their biological functions and roles in disease, it is necessary to extract them from the native membranes. While the amphipathic nature of these bio-macromolecules presents technical challenges, amphiphilic assistants such as detergents serve as useful tools for membrane protein structural and functional studies. Conventional detergents are limited in their ability to maintain the structural integrity of membrane proteins and thus it is essential to develop novel agents with enhanced properties. Here, we designed and characterized a novel class of amphiphiles with vitamin E (<I>i.e.</I>, α-tocopherol) as the hydrophobic tail group and saccharide units as the hydrophilic head group. Designated vitamin E-based glycosides (VEGs), these agents were evaluated for their ability to solubilize and stabilize a set of membrane proteins. VEG representatives not only conferred markedly enhanced stability to a diverse range of membrane proteins compared to conventional detergents, but VEG-3 also showed notable efficacy toward stabilization and visualization of a membrane protein complex. In addition to hydrophile-lipophile balance (HLB) of detergent molecules, the chain length and molecular geometry of the detergent hydrophobic group seem key factors in determining detergent efficacy for membrane protein (complex) stability.</P>
Glucose-Neopentyl Glycol (GNG) amphiphiles for membrane protein study
Chae, Pil Seok,Rana, Rohini R.,Gotfryd, Kamil,Rasmussen, Søren G. F.,Kruse, Andrew C.,Cho, Kyung Ho,Capaldi, Stefano,Carlsson, Emil,Kobilka, Brian,Loland, Claus J.,Gether, Ulrik,Banerjee, Surajit,Byrn The Royal Society of Chemistry 2013 Chemical communications Vol.49 No.23
<P>The development of a new class of surfactants for membrane protein manipulation, “GNG amphiphiles”, is reported. These amphiphiles display promising behavior for membrane proteins, as demonstrated recently by the high resolution structure of a sodium-pumping pyrophosphatase reported by Kellosalo <I>et al.</I> (<I>Science</I>, 2012, 337, 473).</P> <P>Graphic Abstract</P><P>A new class of surfactants, the GNGs, tends to form small protein–detergent complexes, which may be favorable for crystallization. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c2cc36844g'> </P>