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        behavior -- whereas eliminating
        GPR158 activity in chronically
        stressed mice made them resistant
        to depression and the effects of
        stress. Additionally, the activity of
        GPR158 receptor has been also
        linked to prostate cancer.

        Historically, GPR158 hasn’t been
        easy to study. It is called an “orphan
        receptor” because scientists
        haven’t yet identified the molecule
        responsible for turning its signaling
        function “on” in a manner similar
        to flipping a switch. The receptor is
        also considered unusual because,     First author Dipak Patil, PhD, a    “The microscope uses a beam of
        in the brain, unlike most receptors   staff scientist in the Martemyanov   electrons instead of light to image
        in its family, it exists in close    laboratory, says solving the        protein assemblies. The shorter
        association with a protein complex   structure provides many new         wavelength of electrons compared
        called the RGS signaling complex.    insights.                           to light allowed us to visualize our
        RGS is short for “regulator of G                                         sample at near-atomic resolution,”
        protein signaling” and it acts as a   “I am thrilled to see the structure   says structural biologist Professor
        powerful brake on cellular signaling.   of this unique GPCR. It is first   Tina Izard, PhD. Patrick Griffin,
        However, it has been unclear why     of its kind, showing many new       PhD, Scripps Research, Florida
        GPR158 engages it.                   features and offering a path for drug   scientific director, co-authored
                                             development,” Patil says.           the study, applying a structural
        In the new study, solving the                                            proteomic platform technology.
        receptor’s structure offered many    The challenge is now to use the
        insights into how GPR158 works.      information gleaned from the        “The promise of Cryo-EM for
        First, scientists found that it binds   structure to inform the design   achieving significant breakthroughs
        RGS complex in the same way that     of small molecule therapeutics      in solving structures of biomolecules
        many receptors typically engage      to combat depression,               is enormous. Our Institute is firmly
        their conventional transducers,      Martemyanov adds.                   committed to expanding Cryo-EM
        leading to the idea that it employs                                      microscopy, which is made possible
        RGS proteins as means of             He is now exploring several         through the recent acquisition and
        transducing its signal. Second, the   possible approaches, including     installation of a new microscope on
        structure revealed that the receptor   disrupting the two-part           campus.”
        exists as two interconnected copies   arrangement, interfering with
        of the GPR158 proteins stabilized    engagement of RGS complex,          The study was a collaboration
        by phospholipids.                    or by specifically targeting the    including researchers from
                                             cache domain with small, drug-like   Columbia University and Appu
        “These are fat-related molecules     molecular binders. Regardless       Singh, PhD, a structural biologist at
        that effectively staple the two      of the road taken, availability     the Indian Institute of Technology in
        halves of the receptor together”     of structural information should    Kanpur.
        Martemyanov explains.                greatly facilitate drug development
                                             efforts to treat depression,        Story Source:
        Finally, on the other side of the    Martemyanov says.                   Materials provided by Scripps
        receptor that faces outside of the                                       Research Institute. Note: Content
        cell, an unusual module called the   This study was made possible by     may be edited for style and length.
        cache domain was revealed. The       the latest technological advances
        authors believe the cache domain     in microscopy, including freezing   Journal Reference:
        serves as a trap for the molecules   proteins at ultra-cold temperatures   1. Dipak N. Patil et al. Cryo-EM
        that activate GPR158. Cache          and examining their organization    structure of human GPR158
        domains have never been observed     through the lens of powerful        receptor coupled to the RGS7-
        in these types of receptors before,   microscopes, a technique called    Gβ5 signaling complex.
        demonstrating the unique biology of   cryogenic electron microscopy, or   Science, 2021 DOI: 10.1126/
        this orphan receptor.                Cryo-EM.                            science.abl4732



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