Modeling resources


Project description

The current project had been financed by National Science Centre in Poland: SONATA 4 DEC-2012/07/D/NZ1/04244. It is mainly focused on G protein-coupled receptors from the class B: glucagon receptor GCGR, gastric inhibitory polypeptide receptor GIPR, glucagon-like peptide-1 receptor GLP1R, pituitary adenylate cyclase-activating polypeptide 1 receptor PAC1R and vasoactive intestinal polypeptide receptor 1 VIPR1. G protein-coupled receptors [1] are integral membrane proteins involved in G-coupled signal transduction. Their distinct structural features (a seven transmembrane helical bundle) is due to the cellular membrane environment. Cellular membrane [2] is composed mainly from lipids, cholesterol, carbohydrates and proteins. Its exact composition depends on a cell type and its tissue localization and also on external environmental conditions. It is a barrier which allows to control the flow of nutrients, drugs and their metabolites and signaling molecules such as hormones or neurotransmitters. Due to its main component (amphiphilic lipids) biological membrane forms a liquid disorder phase, yet it can be adjusted in certain conditions (e.g. heat) by organisms. Typical physical properties of biological membrane are: hydrophobicity, low permeability, high viscosity and density comparing extracellular environment and negative charge (esp. in mitochondria). The class B GPCRs has recently been characterized by X-ray crystallography [3] and cryo-electron microscopy [4]. References: [1] Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459(7245):356-63. [2] T. Heimburg, Physical properties of biological membranes, H.G. Bohr (Ed.), Handbook of Molecular Biophysics, Wiley-VCH (2009), pp. 593-616. [3] Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, Liu K, Cai X, Dai A, Lin G, Liu D, Wu F, Wu Y, Zhao S, Ye L, Han GW, Lau J, Wu B, Hanson MA, Liu ZJ, Wang MW, Stevens RC. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature. 2017 Jun 8;546(7657):312-315. [4] Liang YL, Khoshouei M, Deganutti G, Glukhova A, Koole C, Peat TS, Radjainia M, Plitzko JM, Baumeister W, Miller LJ, Hay DL, Christopoulos A, Reynolds CA, Wootten D, Sexton PM. Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature. 2018 Sep;561(7724):492-497.

GUT-DOCK

GUT-DOCK has been developed to support data mining in the area of molecular modeling and drug design targeting a distinct environment of cellular membrane and its protein components - G protein-coupled receptors.

GUT-DOCK is a web service designed for docking of small molecules to selected class B G protein-coupled receptors (gut hormone receptors). Gut hormone receptors are expressed mainly in the cellular membrane of the gastrointestinal tract. For more information, please visit the GUT-DOCK website: http://gut-dock.miningmembrane.com.

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