Autoregulation of GPCR signalling through the third intracellular loop

Sadler

The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation1-3. Despite this, the lack of a defined structure of ICL3, combined with its high sequence divergence among GPCRs, complicates characterization of its involvement in receptor signalling4. Previous …

Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations

Lukas Grätz, Maria Kowalski-Jahn, Magdalena M. Scharf, Pawel Kozielewicz, Michael Jahn, Julien Bous, Nevin A. Lambert, David E. Gloriam, Gunnar Schulte

The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis …

Structural basis of odorant recognition by a human odorant receptor

Billesbølle, C.B., de March, C.A., van der Velden, W.J.C. et al.

Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome1-3. How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight …

Multiscale Computational Modeling of the Effects of 2’-deoxy-ATP on Cardiac Muscle Calcium Handling

Marcus T. Hock, Abigail E. Teitgen, Kimberly J. McCabe, Sophia P. Hirakis, Gary A. Huber, Michael Regnier, Rommie E. Amaro, J. Andrew McCammon, Andrew D. McCulloch

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels …

Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric Gs

Lu Xu; Bo Chen; Hannes Schihada; Shane C. Wright; Ainoleena Turku; Yiran Wu; Gye-Won Han; Maria Kowalski-Jahn; Pawel Kozielewicz; Carl-Fredrik Bowin; Xianjun Zhang; Chao Li; Michel Bouvier; Gunnar Schulte; Fei Xu

Residue 6.43 defines receptor function in class F GPCRs

Ainoleena Turku; Hannes Schihada; Pawel Kozielewicz; Carl-Fredrik Bowin; Gunnar Schulte

The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) subtypes and Smoothened (SMO), remains one of the most enigmatic GPCR families. While SMO relies on cholesterol binding to the 7TM core of the receptor to activate downstream signaling, underlying details of receptor activation remain obscure for …

Structural insight into small molecule action on Frizzleds

Kozielewicz P, Turku A, Bowin C-F, Petersen J, Valnohova J, Consuelo Alonso Cañizal M, Ono Y, Inoue A, Hoffmann C, Schulte G

WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, stem cell regulation and tissue homeostasis. FZDs are linked to severe human pathology and are seen as a promising target for therapy. Despite intense efforts, no small molecule drugs with distinct efficacy have emerged. Here, we identify the Smoothened agonist …

DIMERBOW: exploring possible GPCR dimer interfaces

Adrian Garcia-Recio, Gemma Navarro, Rafael Franco, Mireia Olivella, Ramon Guixa-Gonzalez, Arnau Cordomi

G protein-coupled receptors (GPCRs) can form homo-, heterodimers and larger order oligomers that exert different functions than monomers. The pharmacological potential of such complexes is hampered by the limited information available on the type of complex formed and its quaternary structure. Several GPCR structures in the Protein Data Bank display …

GPCRmd uncovers the dynamics of the 3D-GPCRome

Ismael Rodríguez-Espigares, Mariona Torrens-Fontanals, et al.

G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. …

Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin

Giulia Morra, Asghar M Razavi, Kalpana Pandey, Harel Weinstein, Anant K Menon, George Khelashvili

Several class-A G protein-coupled receptor (GPCR) proteins act as constitutive phospholipid scramblases catalyzing the transbilayer translocation of >10,000 phospholipids per second when reconstituted into synthetic vesicles. To address the molecular mechanism by which these proteins facilitate rapid lipid scrambling, we carried out large-scale ensemble atomistic molecular dynamics simulations of the …

Membrane cholesterol access into a G-protein-coupled receptor

R. Guixà-González, J. L. Albasanz, I. Rodriguez-Espigares, M. Pastor, F. Sanz, M. Martí-Solano, M. Manna, H. Martinez-Seara, P. W. Hildebrand, M. Martín, J. Selent

Cholesterol is a key component of cell membranes with a proven modulatory role on the function and ligand-binding properties of G-protein-coupled receptors (GPCRs). Crystal structures of prototypical GPCRs such as the adenosine A2A receptor (A2AR) have confirmed that cholesterol finds stable binding sites at the receptor surface suggesting an allosteric …

Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity

Abhijeet Kapoor, Gerard Martinez-Rosell, Davide Provasi, Gianni de Fabritiis & Marta Filizola

While the therapeutic effect of opioids analgesics is mainly attributed to u-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to b-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond …