4NC5
Human sialidase 2 in complex with 2,3-difluorosialic acid (covalent intermediate)
Summary for 4NC5
| Entry DOI | 10.2210/pdb4nc5/pdb |
| Related | 2A75 2AH2 |
| Descriptor | Sialidase-2, 5-acetamido-3,5-dideoxy-3-fluoro-D-erythro-alpha-L-manno-non-2-ulopyranosonic acid, PHOSPHATE ION, ... (4 entities in total) |
| Functional Keywords | human neuraminidase, sialidase, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 42892.79 |
| Authors | Buchini, S.,Gallat, F.-X.,Greig, I.R.,Kim, J.-H.,Wakatsuki, S.,Chavas, L.M.G.,Withers, S.G. (deposition date: 2013-10-24, release date: 2013-11-06, Last modification date: 2024-10-30) |
| Primary citation | 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 Cited by 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: 24591206DOI: 10.1002/anie.201309675 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.513 Å) |
Structure validation
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