G protein-coupled receptors (GPCRs) play key roles in a variety of signaling cascades that control many cellular processes and are related to numerous diseases, thus much effort is devoted to obtain their functional structures. Construction of applicable GPCR models requires accurate structure determination of extracellular elements, especially the second extracellular loop (ECL2). We applied a well-established protein modeling tool – the CABS model – for structure prediction of three extracellular loops in thirteen GPCRs. The CABS method proved to be accurate during single loop reconstruction [1]. In this study, the long ECL2 loops (of length between 13 and 34 residues) were predicted in an environment of other extracellular loops being fully flexible and transmembrane domain fixed in its X-ray conformation. The modeling procedure utilized theoretical predictions of ECL2 secondary structure and experimental constraints on disulfide bridges. Our approach yielded ensembles of low-energy conformers and the most populated conformers, that contained models close to the available X-ray structures [2]. The modeling results are comparable to other state-of-the-art modeling methods and provide a benchmark of lately reported GPCR structures for assessing other algorithms.

References:

1. Kolinski, M. and Filipek, S., Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations. Journal of molecular modeling, 2010. 16(10): p. 1567-1576.
2. Kmiecik, S. Jamroz, M. and Kolinski, M., Structure prediction of the second extracellular loop in G-protein-coupled receptors. (submitted) 2014.

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1. Characterization of protein structural changes: an efficient modeling approach.