Laboratory of Structural Chemistry and Biology

Research Outline

At the Laboratory of Structural Chemistry and Biology, we use analytical apparatus such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and X-ray crystal structure analysis for the structural analysis of a wide range of biologically active substances found in assay systems and also derivatives of these substances and synthetic compounds.

We have elucidated the basic mechanism of life phenomena using structural biology methods. Furthermore, we are creating a basis for designing more potent drugs that regulate the phenomena through the structural analysis of drug–target complexes.

Theme outline

1. Metabolome analysis of microbial secondary metabolites

Microbial secondary metabolites have diverse chemical structures and biological activities. On the other hand, the discovery of new bioactive substances has become very difficult because of the numerous types of materials that have been found by intensive screening over a long period of time. We have carried out the very small amount dereplication system and an effective search of new bioactive substance has been conducted by the targetnon target screening analysis using high resolution high accuracy apparatus of LTQ Orbitrap LC-MS.

Fig.1 JEOL ECZ600R
Fig.1 JEOL ECZ600R
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Fig.2 Bruker AVANCE III HD 400
Fig.2 Bruker AVANCE III HD 400
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Thermo Fig.3 Bruker AVANCE III 500
Fig.3 Bruker AVANCE III 500
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Fig.4 Thermo Fisher Scientific LTQ Orbitrap
Thermo Fisher Scientific LTQ Orbitrap
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Fig.5 Shimadzu AXIMA TOF2
Fig.5 Shimadzu AXIMA TOF2
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2. Structural biology of autophagy

Autophagy is an intracellular degradation system conserved in eukaryotes. It has various physiological roles and its dysfunction causes various severe diseases such as neurodegeneration and cancer. During autophagy, doublemembrane structures called autophagosomes are generated, which sequester degradation targets and deliver them to the lytic compartment, the lysosome, where they are degraded by hydrolases. Over 40 Atg proteins have been identified as critical factors for autophagy; however, the molecular mechanism of how these Atg proteins mediate each process of autophagy remains to be elucidated. We are attempting to determine the molecular mechanism of autophagy through a comprehensive structural study of Atg proteins and a functional study based on structural information. Based on the structural and functional information obtained, we are developing drugs that regulate autophagy.

Fig.6 Atg protein structures that have been determined
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3. Structural analysis of drug–protein complexes

We are performing structural studies of the physiologically active substances, which were developed in IMC, as a complex with their target proteins using X-ray crystallography. Based on the structural information of the compound–target complex obtained, we are elucidating the mechanism of action for the compounds and designing a new compound that has a higher affinity for the target protein. For example, we are using X-ray crystallography to determine the ternary complex formed between a new anti-MRSA (methicillin-resistantStaphylococcus aureus) drug, DNA gyrase, and DNA.

Fig.7 Rigaku VariMaX with RAPID
Fig.7 Rigaku VariMaX with RAPID
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Fig.8 RIBM Nano Explorer High-Speed Atomic Force Microscopy
Fig.8 RIBM Nano Explorer
High-Speed Atomic Force Microscopy

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