Membrane Channels and Receptors

G protein-coupled Receptors

(contact person, Hugo Gutierrez de Teran)

G protein coupled receptors (GPCRs) are a superfamily of membrane receptors of extraordinarily pharmacological interest, being the main target of more than 30% of the marketed drugs. With the number of experimental GPCR structures growing fast, Computational Biology is playing a major role in the further elucidation of new structures, providing a better understanding receptor dynamics and importantly contributing to the design of new ligands. Our activities in this area is organized around the following topics:
•    GPCR structure prediction: Our pipeline for the modeling and simulation of GPCRs is centralized at the GPCR-ModSim web server.
•    Characterization of the Neuropeptide-Y receptor family and related peptide-binding GPCRs: in collaboration with the Dan Larhammar’s group at the Neurosciences department.
•    Discovery and design of GPCR ligands: We currently focus on the design of potent and selective antagonists for the adenosine receptors, in collaboration with the Combinatorial Chemistry group of Eddy Sotelo, USC.
•    Molecular dynamics and free energy calculations can reveal insights into structure-function and structure-activity relationships: we are working on the characterization of the conformational equilibrium of GPCRs, the mechanism of allosteric control and a computational prediction of the effects of single-point mutations on receptor stability and ligand binding.

List of Publications

Boukharta, L.; Gutiérrez-de-Terán, H.; Åqvist, J. Computational prediction of alanine scanning and ligand binding energetics in G-protein coupled receptors. PlOS Comp. Biol. (2014) 10:exxx (in press).

Gutiérrez-de-Terán, H. The roles of computational chemistry in the ligand design of 
G protein-coupled receptors: how far have we come and what should we expect? Fut. Med. Chem. (2014) 6:251-54.

Gutiérrez-de-Terán, H. ; Massinkc, A.; Rodríguez, D.; Liu, W.; Han, G.W.; Joseph, 
J. S.; Katritch, I.; Heitman, L. H.; Xia, L.; IJzerman, A.; Cherezov, V.; Katritch, V.; Stevens, R. C. The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor. Structure (2013) 21:2175-85.

Xu,B.; Fällmar,H.; Boukharta,L.; Pruner,J.; Lundell,I.;Mohell,N.; Gutiérrez-de-Terán,H.; 
Åqvist, J.; Larhammar, D. Mutagenesis and computational modeling of the human G protein-coupled receptor Y2 for neuropeptide Y and peptide YY Biochemistry (2013) 52:7987-98.

Crespo, A.; El Maatougui, A.; Biagini, P.; Azuaje, J.; Coelho, A.; Brea, P.; Loza, M.I.; Cadavid, M.I.; García-Mera, X.; Gutiérrez-de-Terán, H. and Sotelo, E. Discov- 
ery of 3,4-Dihydropyrimidin-2(1H)-ones as a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists. ACS Med. Chem. Lett. (2013) 4:1031-1036.

 Yaziji, V.; Rodríguez, D.; Coelho, A.; García-Mera, X.; Brea, J.; Loza, M.I.; Cadavid, M.I.; Gutiérrez-de-Terán, H.; Sotelo, E.: Selective and Potent Adenosine A3 Receptor Antagonists by Methoxyaryl Substitution on the N(2,6-Diarylpyrimidin- 4-yl)acetamide scaffold. Eur. J. Med. Chem. (2013) 59:235-42.

Gutiérrez-de-Terán, H.*; Bello, X.; Rodríguez, D. (* corresponding author): Characterization of the dynamic events of GPCRs by automated computational simulations. Biochem. Soc Trans (2013), 41:205-212.

Boukharta, L, Keränen, H, Stary-Weinzinger, A, Wallin, G, de Groot, BL, Aqvist, J.; Computer simulations of structure-activity relationships for HERG channel blockers Biochemistry50, 6146, (2011)

Åkerberg, H., Fällmar, H., Sjödin, P., Boukharta, L., Gutiérrez-de-Terán, H., Lundell, I., Mohell, N., Larhammar, D. Mutagenesis of human neuropeptide Y/peptide YY receptor Y2 reveals additional differences to Y1 in interactions with highly conserved ligand positions Regul. Peptides 163, 120, (2010)

Stary, A., Wacker, S. J., Boukharta, L., Zachariae, U., Karimi-Nejad, Y., Åqvist, J., Vriend, G., de Groot, B. L. Toward a Consensus Model of the hERG Potassium Channel ChemMedChem5, 455, (2010)

Johansson, C., Boukharta, L., Eriksson, J., Åqvist, J., Sundström, L. Mutagenesis and Homology Modeling of the Tn21 Integron Integrase IntI1 Biochemistry48, 1743, (2009)

Andér, M., Luzhkov, V.B., Åqvist, J. Ligand binding to the voltage gated Kv1.5 potassium channel in the open state - docking and computer simulations of a homology model. Biophys. J.94, 820, (2008)

Luzhkov, V., Almlöf, M., Nervall, M., Åqvist, J. Computational Study of Binding Affinity and Selectivity of the Bacterial Ammonium Transporter AmtB. Biochemistry45, 10807, (2006)

Österberg, F., Åqvist, J. Exploring Blocker Binding to a Homology Model of the Open hERG K+ Channel using Docking and Molecular Dynamics Methods. FEBS Lett.579, 2939, (2005)

Luzhkov, V.B., Åqvist, J. Ions and Blockers in Potassium Channels: Insights from Free Energy Simulations. Biochim. Biophys. Acta1747, 109, (2005)

Luzhkov, V.B., Nilsson, J., Århem, P., Åqvist, J. Computational Modeling of the Open-State Kv1.5 Ion Channel Block by Bupivacaine. Biochim. Biophys. Acta1652, 35, (2003)

Luzhkov, V.B., Österberg, F., Åqvist J. Structure-Activity Relationship for Extracellular Block of K+ Channels by Tetraalkylammonium Ions. FEBS Lett.554, 159, (2003)