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Biopharmaceutics(Medical and Health Sciences)

Hino NobumasaAssociate professor / Lecturer

We have the technology to add various functions to proteins by incorporating ‘designer’ amino acids. The in-cell protein photo-cross-linking method, which is an application of this technology, enables us to capture protein-protein interactions that actually occur in living cells. By using this technique, we aim to elucidate the molecular mechanisms by which cellular stimuli regulate epigenetics and the protein-protein interaction networks that are aberrant in cancer cells.

Research theme

Development of a method for introducing designer amino acids into proteins in living cells.

Almost all living organisms in nature synthesize proteins using canonical 20 amino acids. This is because a common rule (genetic code) is used to translate nucleic acid gene sequences into amino acid protein sequences. We have developed a technology to introduce designer amino acids into desired proteins in living cells by rewriting a part of the genetic code to encode the 21th amino acid.

Development and application of in-cell protein photo-cross-linking method.

There are tens of thousands of proteins expressed in mammalian cells. They do not function independently but interact with each other to form a complex network. We have developed an in-cell protein photo-cross-linking method in which a photoreactive amino acid is site-specifically introduced into a protein of interest and covalently capture the proteins that actually interact within the cell. Using this method, we are conducting research to elucidate protein-protein interactions involved in various physiological phenomena and diseases.

Identification of protein-protein interactions that are dysregulated by cancer mutations

In cancer cells, many aberrant proteins expressed from mutated genes disrupt signal transduction process and promote cell growth. By applying the in-cell protein photo-cross-linking technique, we have established a new method to identify protein-protein interactions that can be destructed due to the mutations. We are currently conducting research to elucidate the signaling pathways that contribute to cancer growth and to discover new drug targets.

Development of highly functionalized protein drugs by introducing designer amino acids

Currently, various proteins such as antibodies are used as pharmaceuticals. We are working on the introduction of designer amino acids into such protein drugs, aiming to add value by improving target binding ability and the stability in blood circulation.

Representative achievements

Sakamoto K., Chen L., Miyaoka T., Yamada M., Masutani T., Ishimoto K., Hino N., Nakagawa S., Asano S., Ago Y. “Generation of KS-133 as a Novel Bicyclic Peptide with a Potent and Selective VIPR2 Antagonist Activity that Counteracts Cognitive Decline in a Mouse Model of Psychiatric Disorders”Front Pharmacol. 12:751587 (2021).

Yanagisawa T.,Kuratani M.,Seki E,Hino N.,Sakamoto K.,and Yokoyama S. “Structural Basis for Genetic-Code Expansion with Bulky Lysine Derivatives by an Engineered Pyrrolysyl-tRNA Synthetase” Cell Chem. Biol. 26, 936-949 (2019).

Noguchi Y.T.,Nakamura M.,Hino N.,Nogami J.,Tsuji S.,Sato T.,Zhang L.,Tsujikawa K.,Tanaka T.,Izawa K.,Okada Y.,Doi T.,Kokubo H.,Harada A.,Uezumi A.,Gessler M.,Ohkawa Y.,Fukada S.I. “Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites” Development 20, pii: dev163618 (2019)

Kita A.,Hino N.,Higashi S.,Hirota K.,Narumi R.,Adachi J.,Takafuji K.,Ishimoto K.,Okada Y.,Sakamoto K.,Tomonaga T.,Takashima S.,Mizuguchi H.,Doi T. “Adenovirus vector-based incorporation of a photo-cross-linkable amino acid into proteins in human primary cells and cancerous cell lines” Sci. Rep. 6, 36946 (2016).

Yanagisawa T.,Hino N.,Iraha F.,Mukai T.,Sakamoto K.,Yokoyama S. “Wide-range protein photo-crosslinking achieved by a genetically encoded Nε-(benzyloxycarbonyl)lysine derivative with a diazirinyl moiety” Mol. BioSyst. 8, 1131-1135 (2012).

Hino N.,Oyama M.,Sato A.,Mukai T.,Iraha F.,Hayashi A.,Kozuka-Hata H.,Yamamoyo T.,Yokoyama S.,Sakamoto K. “Genetic incorporation of a photo-crosslinkable amino acid reveals novel protein complexes with GRB2 in mammalian cells” J. Mol. Biol. 406, 343-353 (2011).

Tagami S.,Sekine S.,Kumarevel T.,Hino N.,Murayama Y.,Kamegamori S.,Yamamoto M.,Sakamoto K.,Yokoyama S. “Crystal structure of bacterial RNA polymerase bound with a transcription inhibitor protein” Nature 468, 978-982 (2010).

Hino N.,Hayashi,A.,Sakamoto,K.,and Yokoyama,S. “Site-specific incorporation of non-natural amino acids into proteins in mammalian cells with an expanded genetic code” Nat. Protocols 1, 2957-2962 (2006).

Hino N.,Okazaki Y.,Kobayashi T.,Hayashi,A.,Sakamoto,K.,and Yokoyama,S. “Protein photo-cross-linking in mammalian cells by site-specific incorporation of a photoreactive amino acid” Nat. Methods 2, 201-206 (2005).

Hino N. “A Method for Protein Photo-cross-linking in Living Cells Facilitating Analysis of Physiological Interactions of Proteins” Yakugaku Zasshi 135, 1357-1363 (2015)