Drug Discovery


the receptor core allowing G protein interaction and activation. The solved structure of a novel non-peptide agonist bound to the GLP-1 receptor identified an unpredicted non-peptide agonist binding pocket (Figure 1)1.


Ion channels Ion channels, as the primary means of transport and exchange between cells, are a key subject of research. They critically impact the function of many diseases; however, they are challenging thera- peutic targets because they are very difficult to crys- tallise. Once extracted from their native membrane environment, ion channels’ structures collapse. Cryo-EM can reveal not only the structure of an


ion channel in its native lipid environment but also the various discreet open and closed states, which are critical to understanding ion gating mechanisms. “Cryo-EM is undoubtedly the technique of


choice to use for determining multiple conforma- tion states of ion channels by imaging the proteins in different conditions,” said Carus Lau, postdoc- toral scientist at the Victor Chang Cardiac Research Institute2.


Cryo-EM complements crystallography in unraveling selective sodium channel blockers “Using cryo-EM, we are tackling many targets that otherwise would be impossible to visualise. Nav1.7, for example, is only one of these cases.” (Quote from the SelectScience editorial by Dr Claudio Ciferri, Senior Scientist and Head of Cryo- EM at Genentech.)


Voltage-gated sodium (Nav) channels are targets


of disease mutations, toxins and therapeutic drugs. Mutations in Nav channel subtypes are associated with migraines, epilepsy, pain and cardiac and muscle paralysis syndromes. Channel blockers lack subtype selectivity and have not been well under- stood. In this research the objective was to determine


key structural templates to design selective Nav channel antagonists using spider protoxin-II (ProTx2)3. Cryo-EM analysis independently validated the crystallographic structural model of the receptor


Figure 2 Cryo-EM structures clearly show structural differences of ProTx2 bound to activated (blue, magenta) versus deactivated (black) receptor. Image based on PDB-entry 6n4r and 6n4q created with Pymol by Hans Raaijmakers


Figure 3 Leishmania tarentolae proteasome 20S subunit. Alpha type subunits in yellow, Beta type subunits in green, endopeptidase in orange, GSK3494245 in blue. Images based on PDB-entry 6qm7 created with Pymol by Hans Raaijmakers


Drug Discovery World Winter 2019/20


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