Synergistic Use of GPCR Modeling and SDM Experiments to Understand Ligand Binding

  • Andrew Potterton
  • Alexander Heifetz
  • Andrea Townsend-NicholsonEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)


There is a substantial amount of historical ligand binding data available from site-directed mutagenesis (SDM) studies of many different GPCR subtypes. This information was generated prior to the wave of GPCR crystal structure, in an effort to understand ligand binding with a view to drug discovery. Concerted efforts to determine the atomic structure of GPCRs have proven extremely successful and there are now more than 80 GPCR crystal structure in the PDB database, many of which have been obtained in the presence of receptor ligands and associated G proteins. These structural data enable the generation of computational model structures for all GPCRs, including those for which crystal structures do not yet exist. The power of these models in designing novel ligands, especially those with improved residence times, and for better understanding receptor function can be enhanced tremendously by combining them synergistically with historic SDM ligand binding data. Here, we describe a protocol by which historic SDM binding data and receptor models may be used together to identify novel key residues for mutagenesis studies.

Key words

GPCRs Adenosine receptors Homology modeling Ligand binding Binding kinetics Receptor Site-directed mutagenesis 



This work was supported by the Biotechnology and Biological Sciences Research Council (grant numbers BB/M009513/1 and BB/P004245/1) and by the EU H2020 CompBioMed project (, 675451).


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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Andrew Potterton
    • 1
    • 2
  • Alexander Heifetz
    • 1
    • 2
  • Andrea Townsend-Nicholson
    • 3
    Email author
  1. 1.Structural and Molecular BiologyUniversity College LondonLondonUK
  2. 2.Evotec (UK) Ltd.AbingdonUK
  3. 3.Division of Biosciences, Research Department of Structural and Molecular BiologyUniversity College LondonLondonUK

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