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Drug Discovery


thesis pathway. ACLY is an interesting target for anti-cancer drugs because cancer cells depend on its activity for proliferation. It is also the target against dyslipidaemia and hepatic steatosis. In this research by Nimbus Therapeutics, the structure- activity relationship (SAR) of targets is explained through binding modes of ACLY tetramers. The objective was to study previously undiscov-


ered allosteric ACLY binding site as target for enhanced ‘druggability’ of inhibitors. This was the first ever high-resolution ACLY


structure where cryo-EM, along with computa- tional insights, determined full tetrameric ACLY structure with small molecule ‘druggable’ inhibitor (Figure 4)5.


Hormone receptors Insulin binding Medical advances have made diabetes a manageable disease, providing its sufferers with longer, healthier lives. However, until recently, the binding mode of insulin to its receptor was unknown. Knowing the precise mechanism of binding could lead to the development of more effective therapeutics. “The insulin receptor (IR) is a dimeric protein


that plays a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbo- hydrate metabolism, and modulating brain neuro- transmitter levels. IR dysfunction has been associ- ated with many diseases, including diabetes, can- cer and Alzheimer’s Disease,” said Dr Giovanna Scapin, Senior Principal Scientist, Merck & Co. Dr Scapin has spent years studying insulin and


diabetes. She was also one of the first adopters of cryo-EM. Thanks to single particle analysis, her


Drug Discovery World Winter 2019/20 13


Figure 6:Cryo-EM structure of BK polyomavirus-like particle in complex with single chain antibody. Images of PDB-entry 6GG0 were created with Pymol by Hans Raaijmakers


Figure 7:Cryo-EM structure of the stalled RNC showing Ribosome, 40S light blue, 60S grey mRNA in red, tRNA in green and blue, nascent chain in magenta with the inhibitor PF846 in blue. Image of PDB-entry 6ole created with Pymol by Hans Raaijmakers


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