ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Sunday, 6 January 2013

Paper: Structural basis of ligand recognition in 5-HT3 receptors

The power and insight provided by structural biology into pharmacology can never be underestimated, and significant progress is now possible for previously challenging target systems for structure determination, most notably the GPCRs, which we regularly cover here on the ChEMBL-og. However, there are an increasing number of ion channel and transporter structures being determined. We are probably in sight of the time when the majority of pharmacology for known drugs can be placed in a three-dimensional structure setting. We live in exciting times!

Here is a paper on a further important drug target family - the ligand-gated ion channels - more specifically structural studies on the multimeric ligand-binding extracellular domain. The work involved the engineering of a more tractable homolog (Aplysia AChBP - Aplysia is a sea hare if you are interested) of the human 5HT3 receptor (5HT3R) to become more 5HT3-like in it's ligand binding properties (Pfam: Neur_chan_LBD PF02931). Complexes of this functional surrogate of 5HT3R with serotonin - the natural agonist ligand, and the drug antagonist granisetron were then determined and analysed. This structural surrogate approach has been tried several times previously (e.g. for nicotinic receptor ligands here).

There's some interesting mutagenesis data reported some of the tables, reporting the binding affinities for some of the mutants - this would be great training/validation data for some proteochemometrics studies, and has also got me wondering if there could be some useful general approximate predictive models for ligand-binding differences developed for cSNPs on the back of this sort of data - similar work for presumed protein stability has previously been developed (e.g. here)....

%A D. Kesters
%A A.J. Thompson
%A M. Brams
%A R. van Elk
%A R. Spurny
%A M. Geitmann
%A J.M. Villalgordo
%A A. Guskov
%A D.U. Helena Danielson
%A S.C.R. Lummis
%A A.B. Smit
%A C. Ulens
%T Structural basis of ligand recognition in 5-HT3 receptors
%D 2013
%V 14
%P 49-56


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