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Research Institute

Department of Molecular Pharmacology

 

Member

Director Yasunori Shintani
Laboratory Chief Satoru Yamazaki
Yuya Nishida
Kentaro Otani
Staff Scientist Yusuke Takahashi
Research fellow Tasneem Qaqorh
Kohei Sameshima
Research scientist Issei Yazawa
Kohei Tonai
Graduate Student Eman Elrefaei
Haruka Egami
Takumi Tateno
Research assistant Satomi Kobayashi
Akiko Ogai
Sonoko Adachi

Research

The structure of proteins exerts their function, which is key to understanding evolution and life. Abnormalities in protein function or structure eventually cause human diseases. It is necessary to carry out biochemical experiments that are fine-tuned to the distinct properties of each protein to understand the function and structure of proteins.
We use various methods, including structural biology, biochemistry, pharmacology, genetics, molecular biology, and computational chemistry, to identify rational therapeutic target molecules and investigate their functions and failures in diseases. Our ultimate goal is to create new treatments by fully using them.
Recent research topic is that we identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics. We succeeded in identifying an antibiotic, which is effective against a super drug-resistant strain of Neisseria gonorrhoeae. (published in Nat commun. Doi. 10.1038/s41467-022-34771-y, https://www.eurekalert.org/news-releases/973963)

Specific research projects

  1. Understanding the molecular mechanism modulating the activity of mitochondrial cytochrome coxidase
  2. Structure-based drug design of an allosteric modulator of cytochrome coxidase to treat mitochondrial diseases, heart failure, and infectious diseases
  3. Identification of a novel molecule playing a pivotal role in myocardial inflammation
  4. Development of novel diagnostic tools and therapeutics for intracranial aneurysm

Publication

  1. Nishida Y, Yanagisawa S, Morita R, Shigematsu H, Shinzawa-Itoh K, Yuki H, Ogasawara S, Yamazaki S, Nagao T, Iwamoto T, Nakabayashi C, Qaqorh T, Takahashi Y, Matsumura W, Kamiya K, Harada R, Mizuno N, Kumasaka T, Murata T, Muramoto K, Tosha T, Shiro Y, Honma T, Shigeta Y, Kubo M, Takashima S, Shintani Y# .Conserved allostery buried inside mitochondrial heme-copper oxidases can generate novel antibiotics. Nat commun. 2022;13(1):7591.
  2. Yashirogi S, Nagao T, Nishida Y, Takahashi Y, Tasneem Q, Yazawa I, Katayama T, Kioka H, Matsui TS, Saito S, Masumura Y, Tsukamoto O, Kato H, Ueda H, Yamaguchi O, Yashiro K, Yamazaki S, Takashima S, Shintani Y # . AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP-170. EMBO Rep. 2021;22(1):e50949.
  3. Nagao T, Shintani Y#, Hayashi T, Kioka H, Kato H, Nishida Y, Yamazaki S, Tsukamoto O, Yashirogi S, Yazawaa I, Asano Y, Shinzawa-Itohe K, Imamura H, Suzuki T, Suzuki T, Goto Y, Takashima S. Higd1a improves respiratory function in the models of mitochondrial disorder. FASEB J. 2020;34(1):1859-1871.
  4. Yamada N, Asano Y, Fujita M, Yamazaki S# , Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, Miura K, Ueshima H, Komuro I, Yamagishi M, Horie M, Kawakami K, Furukawa T, Koizumi A, Kurachi Y, Sakata Y, Minamino T, Kitakaze M, Takashima S.. Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation. Circulation. 2019;139:2157-2169.
  5. Shiraishi M, Shintani Y , Shintani Y, Ishida H, Saba R, Yamaguchi A, Adachi H, Yashiro K, Suzuki K. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J Clin Invest. 2016;126(6):2151-66.
  6. Hayashi T, Asano Y, Shintani Y , Aoyama H, Kioka H, Tsukamoto O, Hikita M, Shinzawa-Itoh K, Takafuji K, Higo S, Kato H, Yamazaki S, Matsuoka K, Nakano A, Asanuma H, Asakura M, Minamino T, Goto Y-I, Ogura T, Kitakaze M, Komuro I, Sakata Y, Tsukihara T, Yoshikawa S, Takashima S. Higd1a is a positive regulator of cytochrome c oxidase. Proc Natl Acad Sci USA. 2015;112:1553–1558.
  7. Shintani Y#, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, Suzuki K#. Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. EMBO Rep. 2014;15:438–445.
  8. Shintani Y# , Kapoor A, Kaneko M, Smolenski RT, D'Acquisto F, Coppen SR, Harada-Shoji N, Lee HJ, Thiemermann C, Takashima S, Yashiro K, Suzuki K#. TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc Natl Acad Sci USA. 2013; 110:5109–5114.
  9. Nakano A, Kato H, Watanabe T, Min K-D, Yamazaki S, Asano Y, Seguchi O, Higo S, Shintani Y, Asanuma H, Asakura M, Minamino T, Kaibuchi K, Mochizuki N, Kitakaze M, Takashima S. AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nat Cell Biol. 2010; 12:583–590.
  10. Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S, J-WIND investigators. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet. 2007; 370:1483–1493.
  11. Seguchi O, Takashima S, Yamazaki S, Asakura M, Asano Y, Shintani Y, Wakeno M, Minamino T, Kondo H, Furukawa H, Nakamaru K, Naito A, Takahashi T, Ohtsuka T, Kawakami K, Isomura T, Kitamura S, Tomoike H, Mochizuki N, Kitakaze M. A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart. J Clin Invest. 2007; 117:2812–2824.
  12. Shintani Y, Takashima S, Asano Y, Kato H, Liao Y, Yamazaki S, Tsukamoto O, Seguchi O, Yamamoto H, Fukushima T, Sugahara K, Kitakaze M, Hori M. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling. The EMBO Journal. 2006; 25:3045–3055.

# corresponding author

last updated : 2023/10/06

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