Because of the essential roles they play in cellular processes like signaling and transport, membrane proteins are drug targets with huge potential. But their low expression levels and need to maintain native conformation and solubility after extraction make the characterization of their structure and function — and ultimately, developing drugs that target them — challenging. Find out how NanoTemper makes membrane proteins like G-protein coupled receptors (GPCRs), ion channels, and transporters more accessible for research.

Discover the advantages NanoTemper tools have in helping you overcome challenges in working with membrane proteins


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Screen for conditions that stabilize structure

Structure determination is a very important step in drug design for membrane proteins. To do this, researchers start by extracting enough protein from its native membrane, then screen different detergents and lipids to look for the optimal conditions that keep the protein folded and stable. Here are two examples that show how NanoTemper tools enable fast screening for detergents and viscous additives.



Quickly find detergents that stabilize your membrane proteins

Structural and functional characterization of membrane proteins starts with extracting the protein from its native membrane environment using detergents. But finding the detergent that both solubilizes and preserves stability is difficult. This study applied label-free nanoDSF to rapidly screen 94 detergents by looking at the thermal stability of 9 membrane proteins. The detergents that preserved the proteins’ stability were then used in purification and structural studies.

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Screen very viscous additives prior to crystallization

Membrane proteins are difficult to crystallize because it’s challenging to solubilize them and maintain their native structure outside the membrane environment. The in meso crystallization method uses the lipid cubic phase (LCP) as a membrane-like environment to crystallize the proteins. Just like with buffers and detergents, different types of LCP and additives are screened. This team used nanoDSF as a tool for rapid screening of even very viscous LCP conditions.

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Perform fast, label-free buffer and compound screens with GPCRs


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Study challenging interactions with membrane proteins to improve drug design


Figuring out the role a membrane protein plays in a cellular process requires understanding how it interacts with its ligands. This knowledge also helps in designing drugs that target these processes. The characterization of the interactions with ligands during drug discovery and development with label-free assays and in solution allows researchers to unravel molecular mechanisms and improve drug design.



Improve drug design to target membrane proteins

The human PepT1 transporter plays an important role in drug uptake and transport — which makes it a promising pharmacological target. Using DtpA — a bacterial homolog — this team measured the binding of peptides and drugs to DtpA with label-free MST. The data helped them model and improve drug design for the human transporter. Additionally, they looked at how nanobodies stabilized the transporter for crystallization and structure determination with label-free nanoDSF.

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Identify key ligand binding sites in solution

The NRT1.1 proton-coupled transporter is responsible for nitrogen assimilation and nitrate transport in plants. In nature, it switches between low and high affinity nitrate binding states in response to falling nitrate levels via a process of phosphorylation. To understand this mechanism, researchers used MST to determine how nitrate binding to GFP-fused NRT1.1 in detergent was affected by phosphorylation and point mutations. In combination with crystallography data, they revealed a key amino acid residue for nitrate binding and showed how phosphorylation of the transporter allows it to switch binding states.

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Use Nanodiscs and SMALPs for native characterization

To characterize membrane proteins, researchers start by removing them from their native lipid environment — but this can fundamentally change their structure, and therefore their function. Studying membrane proteins in lipid nanodiscs and SMALPs keeps them in a membrane-like environment where interrogation of their structure and function is possible with methods like nanoDSF and MST. Because the measurements are performed in solution, they have an advantage over other methods that require immobilization to a solid matrix.



Study membrane proteins in lipid nanoparticles

Extraction of membrane proteins from their native lipid environment with detergents often leads to the loss of structurally and functionally important lipids. Lipid nanodiscs offer a way to study these proteins in very close to native conditions. In this study, researchers used nanoDSF to show that reconstitution of membrane proteins into saposin lipid nanoparticles increased their stability when compared to detergent. Label-free MST confirmed that membrane proteins in lipid nanoparticles bound their ligands with the expected affinity, showing that they were folded and functional in this membrane-like environment.

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Discover how membrane composition affects GPCR binding activity

In vivo, the signaling activity of GPCRs is influenced by the lipid composition of their surrounding plasma membrane. Due to the important role GPCRs play as pharmacological targets, we need to understand how lipid composition affects their binding interactions with drugs. Here, researchers used MST to examine the interaction of serotonin with a GPCR, the serotonin receptor, in nanodiscs of different lipid composition, in solution. They revealed that the strength of the affinity of serotonin for its receptor differed depending on the lipid composition of the nanodiscs.

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Study interactions of low expressing GPCRs in native membranes

The human dopamine receptor is a GPCR and a key drug target in the treatment of a variety of neurological and psychiatric disorders. This receptor has very low expression levels in experimental settings, making structural and functional studies is very difficult to achieve. This team successfully extracted the human GPCR from its native lipid environment via detergent-free Lipodisq formation, which retains a near-native membrane environment. They used MST to show for the first time the binding of neurotensin to the human dopamine receptor in its native state.

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