7NL5

Structure of the catalytic domain of the Bacillus circulans alpha-1,6 Mannanase in complex with an alpha-1,6-alpha-manno-cyclophellitol trisaccharide inhibitor

Summary for 7NL5

• Entry DOI: 10.2210/pdb7nl5/pdb
• Descriptor: Alpha-1,6-mannanase, alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose, (1R,6S)-5beta-(Hydroxymethyl)-7-oxabicyclo[4.1.0]heptane-2beta,3beta,4alpha-triol, ... (5 entities in total)
• Functional Keywords: mannanase, cyclophellitol, epoxide, hydrolase
• Biological source: Bacillus circulans
• Total number of polymer chains: 1
• Total formula weight: 41627.51

Authors

Schroeder, S.,Offen, W.A.,Males, A.,Jin, Y.,De Boer, C.,Enotarpi, J.,Marino, L.,van der Marel, G.A.,Florea, B.I.,Codee, J.D.C.,Overkleeft, H.S.,Davies, G.J. (deposition date: 2021-02-22, release date: 2021-04-28, Last modification date: 2024-10-16)

Primary citation

Schroder, S.P.,Offen, W.A.,Males, A.,Jin, Y.,de Boer, C.,Enotarpi, J.,Marino, L.,van der Marel, G.A.,Florea, B.I.,Codee, J.D.C.,Overkleeft, H.S.,Davies, G.J.
Development of Non-Hydrolysable Oligosaccharide Activity-Based Inactivators for Endoglycanases: A Case Study on alpha-1,6 Mannanases.
Chemistry, 27:9519-9523, 2021

PubMed Abstract: There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate-active enzymes. Activity-based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non-hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate-assisted regioselective trans-diaxial epoxide opening of carba-mannal synthesised for this purpose, yields inactivators that act as powerful activity-based inhibitors for α-1,6 endo-mannanases. 3-D structures at 1.35-1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity-based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families.

PubMed: 33878235
DOI: 10.1002/chem.202101255

Experimental method

X-RAY DIFFRACTION (1.4 Å)