Autoregulation of GPCR signalling through the third intracellular loop

Sadler, Fredrik and Ma, Ning and Ritt, Michael and Sharma, Yatharth and Vaidehi, Nagarajan and Sivaramakrishnan, Sivaraj

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 …

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 …

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 …

Plasma membrane preassociation drives β-arrestin coupling to receptors and activation

Grimes, Jak and Koszegi, Zsombor and Lanoiselee, Yann and Miljus, Tamara and O'Brien, Shannon L. and Stepniewski, Tomasz M. and Medel-Lacruz, Brian and Baidya, Mithu and Makarova, Maria and Mistry, Ravi and Goulding, Joelle and Drube, Julia and Hoffmann, Carsten and Owen, Dylan M. and Shukla, Arun K. and Selent, Jana and Hill, Stephen J. and Calebiro, Davide

b-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-b-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in …

Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Manbir Sandhu, Aaron Cho, Ning Ma, Elizaveta Mukhaleva, Yoon Namkung, Sangbae Lee, Soumadwip Ghosh, John H. Lee, David E. Gloriam, Stéphane A. Laporte, M. Madan Babu, Nagarajan Vaidehi

Recent studies have shown that G protein coupled receptors (GPCRs) show selective and promiscuous coupling to different Ga protein subfamilies and yet the mechanisms of the range of coupling preferences remain unclear. Here, we use Molecular Dynamics (MD) simulations on ten GPCR:G protein complexes and show that the location (spatial) …

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 …

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

Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor

Peters, Brandon L. and Deng, Jinxia and Ferguson, Andrew L., Garriga, Pere

G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling …

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 …

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 …