Bioscience

New Basis for Liver Disease Therapy

On Sep. 15, Cancer Research published the latest achievement made by the Research Group lead by Liu Zhijie of the Institute of Biological Physics, CAS in the research of structure and function of protein related to liver disease in the form of cover story entitled “Structural basis for the inhibition of human 5,10-methenyltetrahydrofolate synthetase by N10-substituted folate analogues”. The homo sapiens 5,10-methenyltetrahydrofolate synthetase (hMTHFS, enzyme classification: EC 6.3.3.2) is located at the starting point of one-carbon metabolic pathway and is very important to the regulation of one-carbon metabolism on the downstream of metabolic pathway. The hMTHFS is an important regulation site for aberrant methylation of genome, integrity of DNA and RNA and repair capacity of DNA caused by cancer. Therefore, hMTHFS is also a very promising drug target. Liu Zhijie Research Group investigated four different compound models of this catalyzing enzyme, including the structure of intermediates and product of hMTHFS-ATP-substrate reaction. They revealed the formation of active site in hMTHFS catalytic reaction, important amino acid participating in the catalytic reaction and detailed process of the catalytic reaction for the first time. This research result provided valuable structural information for follow-up structure-based drug design and laid a foundation for the R&D of new drugs to be used in chemotherapy of cancer and treatment of metabolic disease.

New Breakthrough in Research on Structure of Human Protein

Recently, Genes & Development published the latest research result made by the joint laboratory of the Institute of Biological Physics, CAS, Tsinghua University and Nankai University led by Rao Zihe, Member of CAS, in the research of LanCL1 (lanthionine synthetase C-like protein-1) in an article entitled “Structure of Human Lanthionine Synthetase C-like Protein 1 and Its Interaction with Eps8 and Glutathione”. Human LanCL1 is a kind of protein which function has rarely been studied. It is only 15% homologous to prokaryotic LanC (lanthionine cyclase) in sequence. This laboratory obtained the three-dimensional crystal structure of LanCL1 and its compound with glutathione. Through analysis of this structure, they found that this protein may be a molecule that can directly couple the redox state of cell with transduction of signal pathway of growth factor receptor. Further mutation test and vitro SPR (surface plasmon resonance) test proved that LanCL1 can specifically bind to SH3 domain of protein EPS8 (substrate protein 8 of growth factor receptor) related to the signal transduction of growth factor and this interaction is regulated by glutathione. Upon this basis, the cell test also showed that all the mutants able to reduce their interaction with EPS8 can inhibit the differentiation of neurocyte PC12. This research result not only showed the way for in-depth research of the function of LanCL1, but also opened a new research area for the research of signal transduction pathway affecting the differentiation of neurocyte.