Characterization And Simulation Calculations Targeting Two Human-derived Proteins

Protein is an important part of the structure of human cells.Understanding the functional proteins responsible for various life activities in the human body can help us better explore the mysteries of life.In this paper,the two types of proteins,enzyme SHMT2(Human Mitochondrial Serine Hydroxymethyltransferase)and T1R1/T1R3 umami receptor(Taste Receptor Type 1 Member 1/3),are explored in detailThe SHMT2 enzyme is an important drug target in the one-carbon metabolic pathway and plays an prominent role during metabolic reprogramming of various cancer cells.However,an inhibitor that effectively targets SHMT2 has not been described.Therefore,this paper set up a system that directly targets SHMT2,that is,first,27 compounds qualifying as potential SHMT2 inhibitors were selected for biological activity verification through virtual screening of the 210 thousand compounds registered in the Specs database;second,these 27 hits were subjected to quick screening by an in vitro non-competitive kinetic assay of SHMT2 single-enzyme catalysis.This allowed us to identify three compounds featuring strong and non-competitive inhibition of SHMT2:AM-807/42004511(IC50=14.52±4.1665μM),AM-807/40675298(IC50＝94.52±5.8991 μM),AM-807/42004633(IC50＝9.43±0.5646 μM),which provides the basis for the design of more effective inhibitors targeting SHMT2The structure of the T1R1/T1R3 receptor is helpful for the development a new type of healthy and safe umami flavor agent.However,there is still no report on the fine structure of human-derived T1R1/T1R3.Given that homology modeling can provide a mechanism for interaction between umami and T1R1/T1R3 receptors Therefore,we introduced a new enhanced model of T1R1/T1R3 receptor based on the latest template,that is,with the crystal structures of CaSR(5K5S/5K5T),mGluR1(40R2)and mGluR5(6N52),the ECD,7TMD and monomer full-length domains of T1R1/T1R3 subunits were successfully constructed.Compared with mGluR1(1EWK)as the preferred template for T1R1/T1R3_VFTD,the domain structure of the model is expanded and the sequence identity is also significantly improved.This result provides a basis for subsequent structural design and screening of new flavoring agents.