2VL4

Structural and biochemical evidence for a boat-like transition state in beta-mannosidases

Summary for 2VL4

• Entry DOI: 10.2210/pdb2vl4/pdb
• Related: 2JE8 2VJX 2VMF 2VO5 2VOT 2VQT 2VQU
• Descriptor: BETA-MANNOSIDASE, (2S,3S,4R,5R)-2,3,4-TRIHYDROXY-5-HYDROXYMETHYL-PIPERIDINE, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: linear free energy relationship, hydrolase, transition state mimic, mannosidase, glycoside hydrolase
• Biological source: BACTEROIDES THETAIOTAOMICRON
• Total number of polymer chains: 2
• Total formula weight: 199596.46

Authors

Tailford, L.E.,Offen, W.A.,Smith, N.L.,Dumon, C.,Moreland, C.,Gratien, J.,Heck, M.P.,Stick, R.V.,Bleriot, Y.,Vasella, A.,Gilbert, H.J.,Davies, G.J. (deposition date: 2008-01-08, release date: 2008-04-01, Last modification date: 2023-12-13)

Primary citation

Tailford, L.E.,Offen, W.A.,Smith, N.L.,Dumon, C.,Morland, C.,Gratien, J.,Heck, M.P.,Stick, R.V.,Bleriot, Y.,Vasella, A.,Gilbert, H.J.,Davies, G.J.
Structural and Biochemical Evidence for a Boat-Like Transition State in Beta-Mannosidases.
Nat.Chem.Biol., 4:306-, 2008

PubMed Abstract: Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases--an area that is emerging for anticancer therapeutics.

PubMed: 18408714
DOI: 10.1038/NCHEMBIO.81

Experimental method

X-RAY DIFFRACTION (1.9 Å)