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  1. AU="Veli-Pekka Jaakola"
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  1. Article: Nanodisc-Tm: Rapid functional assessment of nanodisc reconstituted membrane proteins by CPM assay

    Ashok, Yashwanth / Veli-Pekka Jaakola

    MethodsX. 2016, v. 3

    2016  

    Abstract: Membrane proteins are generally unstable in detergents. Therefore, biochemical and biophysical studies of membrane proteins in lipidic environments provides a near native-like environment suitable for membrane proteins. However, manipulation of proteins ... ...

    Abstract Membrane proteins are generally unstable in detergents. Therefore, biochemical and biophysical studies of membrane proteins in lipidic environments provides a near native-like environment suitable for membrane proteins. However, manipulation of proteins embedded in lipid bilayer has remained difficult. Methods such as nanodiscs and lipid cubic phase have been developed for easy manipulation of membrane proteins and have yielded significant insights into membrane proteins. Traditionally functional reconstitution of receptors in nanodiscs has been studied with radioligands. We present a simple and faster method for studying the functionality of reconstituted membrane proteins for routine characterization of protein batches after initial optimization of suitable conditions using radioligands. The benefits of the method are•Faster and generic method to assess functional reconstitution of membrane proteins.•Adaptable in high throughput format (≥96 well format).•Stability measurement in near-native lipid environment and lipid dependent melting temperatures.
    Keywords detergents ; lipid bilayers ; lipids ; membrane proteins ; receptors
    Language English
    Size p. 212-218.
    Publishing place Elsevier B.V.
    Document type Article
    ISSN 2215-0161
    DOI 10.1016/j.mex.2016.03.009
    Database NAL-Catalogue (AGRICOLA)

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  2. Article ; Online: Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs

    Toon Laeremans / Zara A. Sands / Pieter Claes / Ann De Blieck / Stephane De Cesco / Sarah Triest / Andreas Busch / David Felix / Abhinav Kumar / Veli-Pekka Jaakola / Christel Menet

    Frontiers in Molecular Biosciences, Vol

    2022  Volume 9

    Abstract: The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug ... ...

    Abstract The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug target class. This is underlined by the fact that approximately 40% of marketed drugs modulate GPCRs. Intriguingly 60% of non-olfactory GPCRs have no drugs or candidates in clinical development, highlighting the continued potential of GPCRs as drug targets. The discovery of small molecules targeting these GPCRs by conventional high throughput screening (HTS) campaigns is challenging. Although the definition of success varies per company, the success rate of HTS for GPCRs is low compared to other target families (Fujioka and Omori, 2012; Dragovich et al., 2022). Beyond this, GPCR structure determination can be difficult, which often precludes the application of structure-based drug design approaches to arising HTS hits. GPCR structural studies entail the resource-demanding purification of native receptors, which can be challenging as they are inherently unstable when extracted from the lipid matrix. Moreover, GPCRs are flexible molecules that adopt distinct conformations, some of which need to be stabilized if they are to be structurally resolved. The complexity of targeting distinct therapeutically relevant GPCR conformations during the early discovery stages contributes to the high attrition rates for GPCR drug discovery programs. Multiple strategies have been explored in an attempt to stabilize GPCRs in distinct conformations to better understand their pharmacology. This review will focus on the use of camelid-derived immunoglobulin single variable domains (VHHs) that stabilize disease-relevant pharmacological states (termed ConfoBodies by the authors) of GPCRs, as well as GPCR:signal transducer complexes, to accelerate drug discovery. These VHHs are powerful tools for supporting in vitro screening, deconvolution of complex GPCR pharmacology, and structural biology ...
    Keywords active state ; biosensor ; ConfoBody ; conformation ; conformer ; GPCR ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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