4NCS

Human sialidase 2 in complex with 2,3-difluorosialic acid (covalent intermediate)

4NCS の概要

• エントリーDOI: 10.2210/pdb4ncs/pdb
• 関連するPDBエントリー: 2A75 2AH2 4NC5
• 分子名称: Sialidase-2, (2S,3S,4R,5R,6R)-5-acetamido-2,3-bis(fluoranyl)-4-oxidanyl-6-[(1S,2S)-1,2,3-tris(oxidanyl)propyl]oxane-2-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: sialidase, human neuraminidase, fluoro-sialic acid, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42894.78

構造登録者

Buchini, S.,Gallat, F.-X.,Greig, I.R.,Kim, J.-H.,Wakatsuki, S.,Chavas, L.M.G.,Withers, S.G. (登録日: 2013-10-25, 公開日: 2013-12-25, 最終更新日: 2023-09-20)

主引用文献

Buchini, S.,Gallat, F.X.,Greig, I.R.,Kim, J.H.,Wakatsuki, S.,Chavas, L.M.,Withers, S.G.
Tuning mechanism-based inactivators of neuraminidases: mechanistic and structural insights.
Angew.Chem.Int.Ed.Engl., 53:3382-3386, 2014

PubMed Abstract: 3-Fluorosialosyl fluorides are inhibitors of sialidases that function by the formation of a long-lived covalent active-site adduct and have potential as therapeutics if made specific for the pathogen sialidase. Surprisingly, human Neu2 and the Trypanosoma cruzi trans-sialidase are inactivated more rapidly by the reagent with an equatorial fluorine at C3 than by its axial epimer, with reactivation following the same pattern. To explore a possible stereoelectronic basis for this, rate constants for spontaneous hydrolysis of the full series of four 3-fluorosialosyl fluorides were measured, and ground-state energies for each computed. The alpha (equatorial) anomeric fluorides hydrolyze more rapidly than their beta anomers, consistent with their higher ground-state energies. However ground-state energies do not explain the relative spontaneous reactivities of the 3-fluoro-epimers. The three-dimensional structures of the two 3-fluoro-sialosyl enzyme intermediates of human Neu2 were solved, revealing key stabilizing interactions between Arg21 and the equatorial, but not the axial, fluorine. Because of changes in geometry these interactions will increase at the transition state, likely explaining the difference in reaction rates.

PubMed: 24591206
DOI: 10.1002/anie.201309675

実験手法

X-RAY DIFFRACTION (2.201 Å)