7SLI

Engineered sperm whale myoglobin-based carbene transferase MbBTIC-C2

7SLI の概要

• エントリーDOI: 10.2210/pdb7sli/pdb
• 分子名称: Myoglobin, PROTOPORPHYRIN IX CONTAINING FE, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: metalloprotein, myoglobin, heme, transferase, oxygen transport, oxygen storage
• 由来する生物種: Physeter catodon (Sperm whale)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18607.97

構造登録者

Jenkins, J.L.,Vargas, D.,Ren, X.,Fasan, R. (登録日: 2021-10-24, 公開日: 2023-05-03, 最終更新日: 2024-05-29)

主引用文献

Vargas, D.A.,Ren, X.,Sengupta, A.,Zhu, L.,Roy, S.,Garcia-Borras, M.,Houk, K.N.,Fasan, R.
Biocatalytic strategy for the construction of sp 3 -rich polycyclic compounds from directed evolution and computational modelling.
Nat.Chem., 16:817-826, 2024

PubMed Abstract: Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles. Two carbene transferases with complementary regioisomer selectivity were evolved to catalyse the stereoselective cyclization of benzothiophene substrates bearing diazo ester groups at the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were elucidated by a combination of crystallographic and computational analyses. Leveraging these insights, the substrate scope of one of the biocatalysts could be expanded to include previously unreactive substrates, highlighting the value of integrating evolutionary and rational strategies to develop enzymes for new-to-nature transformations. The molecular scaffolds accessed here feature a combination of three-dimensional and stereochemical complexity with 'rule-of-three' properties, which should make them highly valuable for fragment-based drug discovery campaigns.

PubMed: 38351380
DOI: 10.1038/s41557-023-01435-3

実験手法

X-RAY DIFFRACTION (2 Å)