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Docking and rolling

SBKB [doi:10.1038/sbkb.2011.42]
Featured Article - October 2011
Short description: GPCR Dock 2010 reveals just how far homology modeling has come and how far it still has to go.

CXCR4 with bound IT1t, PDB code 3OE9. Image provided by S. Jähnichen on Wikimedia Commons.

One of the most rapidly growing areas of structural biology is the determination of G protein–coupled receptor (GPCR) structures, and with good cause. GPCRs mediate a wide variety of biological responses, making understanding their activity essential for a range of diseases and conditions. However, only a small representation of the larger GPCR family has been subjected to three-dimensional structure determination. This makes homology modeling an essential technique for unraveling the complex biological activities of other family members. Despite their relative similarity, the mechanism of ligand binding by GPCRs can vary greatly from one receptor to the next, even for closely related structures. Using molecular modeling approaches to gain a clear picture of how ligands interact with their receptors is therefore of utmost importance.

The goal of the GPCR Dock Assessment of 2010, hosted by the Scripps Institute and UCSD and now reported by Stevens, Abagyan and colleagues, was to assess the ability of the modeling community to determine the structure and ligand-binding mechanisms of two GPCRs. Thirty-five groups from around the world submitted a total of 275 structures to model (i) the dopamine D3 receptor with bound eticlopride, (ii) CXCR4 with bound IT1t, or (iii) CXCR4 with a bound CVX15 peptide. Models were assessed against the crystal structures of those complexes, which had been solved at the time of the assessment, but were not yet published.

Results of the assessment clearly demonstrated that closely related structures (approximately 35–40% sequence identity) are a modeler's best friend, as participants had the most success modeling the D3 receptor with eticlopride. Some of the best models even produced results that reached the level of accuracy expected from experimental approaches. However, flexible and variable loops still proved difficult to predict accurately. In the case of the CXCR4 models, working from a more distantly related homology template was not as successful, as submitted models varied much more from the structures, particularly with regard to ligand interactions. Part of the challenge was unique to CXCR4 itself, which, as part of a different GPCR subfamily, contains a larger pocket that made it difficult to model the protein–ligand interactions correctly. This was especially the situation with modeling the complex of CXCR4 with CVX15, which proved challenging for all the participants. Additionally, it was evident that although computational modeling approaches are useful, the most productive approach is not purely computational, but rather an efficient symbiosis of modeling, biochemistry, and human expertise.

In the end, GPCR Dock 2010 revealed that, for some receptors, molecular modeling may be ready to serve as a viable alternative to experimental approaches. This is tempered, though, by the finding that further work is needed to develop improved methods to handle more difficult situations. It will be interesting to see how researchers respond to the results of the challenge as they tackle future rounds of GPCR Dock assessment.

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  1. I. Kufareva et al. Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 Assessment.
    Structure 19, 1108-1126 (2011). doi:10.1016/j.str.2011.05.012

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