Journal article

INPHARMA-Based Determination of Ligand Binding Modes at alpha(1)-Adrenergic Receptors Explains the Molecular Basis of Subtype Selectivity

Tasneem M Vaid, David K Chalmers, Daniel J Scott, Paul R Gooley



The structural poses of ligands that bind weakly to protein receptors are challenging to define. In this work we have studied ligand interactions with the adrenoreceptor (AR) subtypes, α1A -AR and α1B -AR, which belong to the G protein-coupled receptor (GPCR) superfamily, by employing the solution-based ligand-observed NMR method interligand NOEs for pharmacophore mapping (INPHARMA). A lack of receptor crystal structures and of subtype-selective drugs has hindered the definition of the physiological roles of each subtype and limited drug development. We determined the binding pose of the weakly binding α1A -AR-selective agonist A-61603 relative to an endogenous agonist, epinephrine, at both ..

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Awarded by NHMRC

Funding Acknowledgements

We would like to thank Feng-Jie Wu (The University of Melbourne) for assistance with optimizing the expression and purification of receptor samples. We are grateful to LisaM. Williams and Riley Cridge (The Florey Institute) for assistance with the binding assays. We would also like to thank Prof. Christian Griesinger, Dr. Dirk Bockelmann and Dr. Pablo Trigo Mourino from the Max Planck Institute for Biophysical Chemistry, Gottingen, for kindly providing us with the SpINPHARMA software, which arose from a collaboration between the MPI and EMBL (Prof. Teresa Carlomagno). This work was supported by NHMRC project grants 1081801 (D.J.S), 1081844 (P.R.G., D.J.S.) and 1141034 (D.J.S., P.R.G.). D.J.S. is an NHMRC Boosting Dementia Research Leadership Fellow. T.M.V. was supported by a Melbourne International Fee Remission Scholarship (MIFRS) and a Melbourne International Research Scholarship (MIRS).