Structure prediction of the second extracellular loop in G-protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) play key roles in living organisms. Therefore it is important to determine their functional structures. The second extracellular loop (ECL2) is a functionally important region of GPCRs which poses significant challenge for computational structure prediction methods. In this work, we evaluated CABS, a well-established protein modeling tool for predicting ECL2 structure in thirteen GPCRs. The ECL2s (with between 13 and 34 residues) are predicted in an environment of other extracellular loops being fully flexible and the 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. Predicted loop fragments resemble X-ray structures with comparable accuracy to those obtained by other state-of-the-art methods. Our results extend other studies by including newly crystallized GPCRs.