Maryam Khoshouei

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta… Mehr anzeigen

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function. Weniger anzeigen

Draper-Joyce CJ, Khoshouei M, Thal DM, Liang YL, Nguyen ATN, Furness SGB, Venugopal H, Baltos JA, Plitzko JM, Danev R, Baumeister W, May LT, Wootten D, Sexton PM, Glukhova A, Christopoulos A.

Authors: Yi-Lynn Liang, Maryam Khoshouei, Alisa Glukhova, Sebastian G. B. Furness, Peishen Zhao, Lachlan Clydesdale, Cassandra Koole, Tin T. Truong, David M. Thal, Saifei Lei, Mazdak Radjainia, Radostin Danev, Wolfgang Baumeister, Ming-Wei Wang, Laurence J. Miller, Arthur Christopoulos, Patrick M. Sexton & Denise Wootten

The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity1. Endogenous and mimetic GLP-1… Mehr anzeigen

Authors: Yi-Lynn Liang, Maryam Khoshouei, Alisa Glukhova, Sebastian G. B. Furness, Peishen Zhao, Lachlan Clydesdale, Cassandra Koole, Tin T. Truong, David M. Thal, Saifei Lei, Mazdak Radjainia, Radostin Danev, Wolfgang Baumeister, Ming-Wei Wang, Laurence J. Miller, Arthur Christopoulos, Patrick M. Sexton & Denise Wootten

The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity1. Endogenous and mimetic GLP-1 peptides exhibit biased agonism—a difference in functional selectivity—that may provide improved therapeutic outcomes1. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gαs heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure2. At the intracellular face, there was a six-degree difference in the angle of the Gαs–α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gαs protein. Our structure provides insights into the molecular basis of biased agonism. Weniger anzeigen

Our understanding of archaeal virus diversity and structure is just beginning to emerge. Here we describe a new archaeal virus, tentatively named Metallosphaera turreted icosahedral virus (MTIV), that was isolated from an acidic hot spring in Yellowstone National Park, USA. Two strains of the virus were identified and were found to replicate in an archaeal host species closely related to Metallosphaera yellowstonensis. Each strain encodes a 9.8- to 9.9-kb linear double-stranded DNA (dsDNA)… Mehr anzeigen

Our understanding of archaeal virus diversity and structure is just beginning to emerge. Here we describe a new archaeal virus, tentatively named Metallosphaera turreted icosahedral virus (MTIV), that was isolated from an acidic hot spring in Yellowstone National Park, USA. Two strains of the virus were identified and were found to replicate in an archaeal host species closely related to Metallosphaera yellowstonensis. Each strain encodes a 9.8- to 9.9-kb linear double-stranded DNA (dsDNA) genome with large inverted terminal repeats. Each genome encodes 21 open reading frames (ORFs). The ORFs display high homology between the strains, but they are quite distinct from other known viral genes. The 70-nm-diameter virion is built on a T=28 icosahedral lattice. Both single particle cryo-electron microscopy and cryotomography reconstructions reveal an unusual structure that has 42 turret-like projections: 12 pentameric turrets positioned on the icosahedral 5-fold axes and 30 turrets with apparent hexameric symmetry positioned on the icosahedral 2-fold axes. Both the virion structural properties and the genome content support MTIV as the founding member of a new family of archaeal viruses. Weniger anzeigen

Sixty years ago the first protein structure was determined by John Kendrew and his colleagues, that of myoglobin; haemoglobin followed shortly thereafter. For quite some time it seemed that only X-ray crystallography would be capable of determining the structure of proteins to high resolution. In recent years, cryo- electron microscopy has emerged as a viable alternative and indeed in many cases the preferred approach. It is capable of studying proteins which span a size range from several… Mehr anzeigen

Sixty years ago the first protein structure was determined by John Kendrew and his colleagues, that of myoglobin; haemoglobin followed shortly thereafter. For quite some time it seemed that only X-ray crystallography would be capable of determining the structure of proteins to high resolution. In recent years, cryo- electron microscopy has emerged as a viable alternative and indeed in many cases the preferred approach. It is capable of studying proteins which span a size range from several megadaltons to proteins as small as myoglobin and haemoglobin. Weniger anzeigen

Authors: Yi-Lynn Liang, Maryam Khoshouei, Mazdak Radjainia, Yan Zhang, Alisa Glukhova, Jeffrey Tarrasch, David M. Thal, Sebastian G. B. Furness, George Christopoulos, Thomas Coudrat, Radostin Danev, Wolfgang Baumeister, Laurence J. Miller, Arthur Christopoulos, Brian K. Kobilka, Denise Wootten, Georgios Skiniotis & Patrick M. Sexton