报告题目1：Design of bioswitches and cell robots for metabolic engineering and synthetic biology
报 告 人：曾安平 教授，德国汉堡工业大学(TUHH)
联 系 人：杨广宇 firstname.lastname@example.org
报告摘要：Despite impressive progresses in systems metabolic engineering and synthetic biology there are still several unsolved major problems in their practical applications for developing effective metabolic pathways and microorganisms, e.g. 1. identification of targets for advanced pathway engineering of productive strains under industrially relevant and in vivo conditions; 2. effective means with proper dynamic range and sensitivity for dynamic control of metabolic pathways; 3. designed elements or devices from synthetic biology often not work well within the host cells, especially for highly productive strains; 4. mathematical models of cellular processes often miss regulatory details inside cells and thus fail to guide biomolecular and cellular design. In this presentation, I will illustrate some of our recent efforts to address these questions. First, I will present results on rational design of bioswitches (riboswitch and ligand-introduced allosteric regulation) with improved dynamic range and sensitivity for dynamic control of metabolic pathways. Then, I will address the question how we can use the cells as massive and highly sensitive “robots” to identify targets, evaluate designed parts and even to evolve the best design for a specific purpose? An automated loop system for global and intelligent optimization of enzymes will also be introduced.
报告题目2：Human GLP-1R crystal structure and allosteric modulation
报 告 人：宋高洁 副研究员, 上海科技大学ihuman研究所
联 系 人：吴更 email@example.com
报告摘要：GLP-1R is a well-recognized drug target for type 2 diabetes, exemplified by several peptidic therapeutic agents on the market, with combined sales of several billions of dollars each year. Orally available small molecule therapeutics have been vigorously sought after by many pharmaceutical companies for several decades to replace the peptides. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators (NAMs), respectively. The structures reveal a common binding pocket for NAMs, present in both GLP-1R and GCGR, and located outside of helices V–VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI. Molecular modeling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G protein coupling. This result provided a template for the structure-based design of novel allosteric modulators and SAR investigations in the context of GLP-1R.