News
Discovery and characterization of small-molecule TGR5 ligands with agonistic activity
Papadopoulos, M. Giovanna E. and Perhal, Alexander F. and Medel-Lacruz, Brian and Ladurner, Angela and Selent, Jana and Dirsch, Verena M. and Kolb, Peter
The Takeda G protein-coupled receptor 5 (TGR5) is activated endogenously by primary and secondary bile acids. This receptor is considered a candidate target for addressing inflammatory and metabolic disorders. We have targeted TGR5 with structure-based methods for ligand finding using the recently solved experimental structures, as well as structures obtained …
Thermodynamic Role of Receptor Phosphorylation Barcode in Cannabinoid Receptor Desensitization
Heo, Eun Ha and Abrol, Ravinder
The endocannabinoid signaling system is comprised of CB1 and CB2 G protein-coupled receptors (GPCRs). CB2 receptor subtype is predominantly expressed in the immune cells and signals through its transducer proteins (Gi protein and β-arrestin-2). Arrestins are signaling proteins that bind to many GPCRs after receptor phosphorylation to terminate G protein …
Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor
Lorenza Pirona, Federico Ballabio, Mercedes Alfonso-Prieto, Riccardo Capelli
Conformational changes as well as molecular determinants related to the activation and inactivation of olfactory receptors are still poorly understood due to the intrinsic difficulties in the structural determination of this GPCR family. Here, we perform, for the first time, the in silico inactivation of human olfactory receptor OR51E2, highlighting …
Structural basis of frizzled 7 activation and allosteric regulation
Bous, Julien and Kinsolving, Julia and Gratz, Lukas and Scharf, Magdalena M. and Voss, Jan Hendrik and Selcuk, Berkay and Adebali, Ogun and Schulte, Gunnar
Frizzleds (ten paralogs: FZD1-10) belong to the class F of G protein-coupled receptors (GPCRs), which remains poorly understood despite its crucial role in multiple key biological functions including embryonic development, stem cell regulation, and homeostasis in the adult. FZD7, one of the most studied members of the family, is more …
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 …
Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling
Marie-Lise Jobin, Véronique De Smedt-Peyrusse, Fabien Ducrocq, Rim Baccouch, Asma Oummadi, Maria Hauge Pedersen, Brian Medel-Lacruz, Maria-Florencia Angelo, Sandrine Villette, Pierre Van Delft, Laetitia Fouillen, Sébastien Mongrand, Jana Selent, Tarson Tolentino-Cortez, Gabriel Barreda-Gómez, Stéphane Grégoire, Elodie Masson, Thierry Durroux, Jonathan A. Javitch, Ramon Guixà-González, Isabel D. Alves, Pierre Trifilieff
Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major …
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 …
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 …
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 …
Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
Mithu Baidya; Madhu Chaturvedi; Hemlata Dwivedi-Agnihotri; Ashutosh Ranjan; Dominic Devost; Yoon Namkung; Tomasz Maciej Stepniewski; Shubhi Pandey; Minakshi Baruah; Bhanupriya Panigrahi; Parishmita Sarma; Manish K. Yadav; Jagannath Maharana; Ramanuj Banerjee; Kouki Kawakami; Asuka Inoue; Jana Selent; Stéphane Laporte; Terence E. Hébert and Arun K. Shukla
Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of b-arrestin (barr) recruitment and trafficking. For several GPCRs such as the vasopressin receptor subtype 2 (V2R), agonist-stimulation first drives the translocation of barrs to the plasma membrane, followed by endosomal trafficking, which is generally considered to be orchestrated …
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 …
A molecular sensor for cholesterol in the human serotonin 1A receptor
Kumar, G. Aditya and Sarkar, Parijat and Stepniewski, Tomasz Maciej and Jafurulla, Md. and Singh, Shishu Pal and Selent, Jana and Chattopadhyay, Amitabha
The function of several G protein-coupled receptors (GPCRs) exhibits cholesterol sensitivity. Cholesterol sensitivity of GPCRs could be attributed to specific sequence and structural features, such as the cholesterol recognition/interaction amino acid consensus (CRAC) motif, that facilitate their cholesterol-receptor interaction. In this work, we explored the molecular basis of cholesterol sensitivity …
Analysis of L-DOPA and droxidopa binding to human β2-adrenergic receptor
Biswas, AD; Catte, A; Mancini, G; Barone, V.
Over the last two decades, an increasing number of studies has been devoted to a deeper understanding of the molecular process involved in the binding of various agonists and antagonists to active and inactive conformations of b2-adrenergic receptor (b2AR). The 3.2 A x-ray crystal structure of human b2AR active state …
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 …
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. …
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 …
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 …
