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      From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins

      Author(s): 1 , 1
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      Journal: Biochemical Society Transactions
      Publisher: Portland Press Ltd.

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          Abstract

          For over a decade, pepducins have been utilized to develop unique pharmacological profiles that have been particularly challenging for traditional drug discovery methods. It is becoming increasingly clear that these cell-penetrating lipopeptides can access receptor conformations that are currently not accessible through orthosteric targeting. This review addresses the emerging concepts in the development of pepducins including the elicitation of biased signalling, pepducin polypharmacology and recent insight into their mechanism of action.

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          The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints.

          Robert Fredriksson, Malin Lagerström, Lars-Gustav Lundin … (2003)
          The superfamily of G-protein-coupled receptors (GPCRs) is very diverse in structure and function and its members are among the most pursued targets for drug development. We identified more than 800 human GPCR sequences and simultaneously analyzed 342 unique functional nonolfactory human GPCR sequences with phylogenetic analyses. Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system. The rhodopsin family is the largest and forms four main groups with 13 sub-branches. Positions of the GPCRs in chromosomal paralogons regions indicate the importance of tetraploidizations or local gene duplication events for their creation. We also searched for "fingerprint" motifs using Hidden Markov Models delineating the putative inter-relationship of the GRAFS families. We show several common structural features indicating that the human GPCRs in the GRAFS families share a common ancestor. This study represents the first overall map of the GPCRs in a single mammalian genome. Our novel approach of analyzing such large and diverse sequence sets may be useful for studies on GPCRs in other genomes and divergent protein families.
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            PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells.

            Adrienne Boire, Lidija Covic, Anika Agarwal … (2005)
            Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors that play critical roles in thrombosis, inflammation, and vascular biology. PAR1 is proposed to be involved in the invasive and metastatic processes of various cancers. However, the protease responsible for activating the proinvasive functions of PAR1 remains to be identified. Here, we show that expression of PAR1 is both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft model. Further, we show that the matrix metalloprotease, MMP-1, functions as a protease agonist of PAR1 cleaving the receptor at the proper site to generate PAR1-dependent Ca2+ signals and migration. MMP-1 activity is derived from fibroblasts and is absent from the breast cancer cells. These results demonstrate that MMP-1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.
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              Structure of a nanobody-stabilized active state of the β2 adrenoceptor

              Søren G F Rasmussen, Hee Jung Choi, Juan Fung … (2011)
              G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviors in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human β2 adrenergic receptor (β2AR) that exhibits G protein-like behavior, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive β2AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11Å outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.
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                Author and article information

                Journal
                Title: Biochemical Society Transactions
                Publisher: Portland Press Ltd.
                ISSN (Print): 0300-5127
                ISSN (Electronic): 1470-8752
                Publication date Created: April 11 2016
                Publication date Created: April 15 2016
                Publication date (Electronic): April 11 2016
                Publication date (Print): April 15 2016
                Volume: 44
                Issue: 2
                Pages: 555-561
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
                Article
                DOI: 10.1042/BST20150230
                SO-VID: 9d38fbf2-2995-41e9-9f22-341076b07131
                Copyright © © 2016
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