6U0Q

Transthyretin in complex with (E)-5,5'-(ethene-1,2-diyl)bis(1,1-dihydroxy-3-oxo-1,3-dihydrobenzo[c][1,2]oxaborol-1-uide)

6U0Q の概要

• エントリーDOI: 10.2210/pdb6u0q/pdb
• 分子名称: Transthyretin, 3-[(~{E})-2-[7,7-bis(oxidanyl)-9-oxidanylidene-8-oxa-7-boranuidabicyclo[4.3.0]nona-1,3,5-trien-3-yl]ethenyl]-7,7-bis(oxidanyl)-8-oxa-7-boranuidabicyclo[4.3.0]nona-1(6),2,4-trien-9-one (3 entities in total)
• 機能のキーワード: ttr, boronic acid, covalent inhibitor, transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28524.88

構造登録者

Windsor, I.W.,Graham, B.J.,Raines, R.T. (登録日: 2019-08-14, 公開日: 2021-01-27, 最終更新日: 2024-10-16)

主引用文献

Graham, B.J.,Windsor, I.W.,Gold, B.,Raines, R.T.
Boronic acid with high oxidative stability and utility in biological contexts.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols. After considering the mechanism and kinetics of the oxidation reaction, we reasoned that diminishing electron density on boron could enhance oxidative stability. We found that a boralactone, in which a carboxyl group serves as an intramolecular ligand for the boron, increases stability by 10-fold. Computational analyses revealed that the resistance to oxidation arises from diminished stabilization of the p orbital of boron that develops in the rate-limiting transition state of the oxidation reaction. Like simple boronic acids and boronate esters, a boralactone binds covalently and reversibly to 1,2-diols such as those in saccharides. The kinetic stability of its complexes is, however, at least 20-fold greater. A boralactone also binds covalently to a serine side chain in a protein. These attributes confer unprecedented utility upon boralactones in the realms of chemical biology and medicinal chemistry.

PubMed: 33653951
DOI: 10.1073/pnas.2013691118

実験手法

X-RAY DIFFRACTION (1.75 Å)