4nc5

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4nc5, resolution 2.51Å ()
Ligands: ,
Gene: NEU2 (HUMAN)
Activity: Exo-alpha-sialidase, with EC number 3.2.1.18
Related: 2a75, 2ah2


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

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

Publication Abstract from PubMed

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.

Tuning mechanism-based inactivators of neuraminidases: mechanistic and structural insights., Buchini S, Gallat FX, Greig IR, Kim JH, Wakatsuki S, Chavas LM, Withers SG, Angew Chem Int Ed Engl. 2014 Mar 24;53(13):3382-6. doi: 10.1002/anie.201309675., Epub 2014 Mar 3. PMID:24591206

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Function

[NEUR2_HUMAN] Hydrolyzes sialylated compounds.

About this Structure

4nc5 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA.

See Also

Reference

  • Buchini S, Gallat FX, Greig IR, Kim JH, Wakatsuki S, Chavas LM, Withers SG. Tuning mechanism-based inactivators of neuraminidases: mechanistic and structural insights. Angew Chem Int Ed Engl. 2014 Mar 24;53(13):3382-6. doi: 10.1002/anie.201309675., Epub 2014 Mar 3. PMID:24591206 doi:http://dx.doi.org/10.1002/anie.201309675

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