2vr4
From Proteopedia
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'''TRANSITION-STATE MIMICRY IN MANNOSIDE HYDROLYSIS: CHARACTERISATION OF TWENTY SIX INHIBITORS AND INSIGHT INTO BINDING FROM LINEAR FREE ENERGY RELATIONSHIPS AND 3-D STRUCTURE''' | '''TRANSITION-STATE MIMICRY IN MANNOSIDE HYDROLYSIS: CHARACTERISATION OF TWENTY SIX INHIBITORS AND INSIGHT INTO BINDING FROM LINEAR FREE ENERGY RELATIONSHIPS AND 3-D STRUCTURE''' | ||
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| + | ==Overview== | ||
| + | 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. | ||
==About this Structure== | ==About this Structure== | ||
2VR4 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_thetaiotaomicron Bacteroides thetaiotaomicron]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VR4 OCA]. | 2VR4 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_thetaiotaomicron Bacteroides thetaiotaomicron]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VR4 OCA]. | ||
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| + | ==Reference== | ||
| + | Structural and biochemical evidence for a boat-like transition state in beta-mannosidases., Tailford LE, Offen WA, Smith NL, Dumon C, Morland C, Gratien J, Heck MP, Stick RV, Bleriot Y, Vasella A, Gilbert HJ, Davies GJ, Nat Chem Biol. 2008 May;4(5):306-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18408714 18408714] | ||
[[Category: Bacteroides thetaiotaomicron]] | [[Category: Bacteroides thetaiotaomicron]] | ||
[[Category: Beta-mannosidase]] | [[Category: Beta-mannosidase]] | ||
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[[Category: Gilbert, H J.]] | [[Category: Gilbert, H J.]] | ||
[[Category: Gratien, J.]] | [[Category: Gratien, J.]] | ||
| - | [[Category: Heck, M.]] | + | [[Category: Heck, M P.]] |
[[Category: Moreland, C.]] | [[Category: Moreland, C.]] | ||
[[Category: Offen, W A.]] | [[Category: Offen, W A.]] | ||
| - | [[Category: Smith, N.]] | + | [[Category: Smith, N L.]] |
[[Category: Stick, R V.]] | [[Category: Stick, R V.]] | ||
| - | [[Category: Tailford, L | + | [[Category: Tailford, L E.]] |
[[Category: Vasella, A.]] | [[Category: Vasella, A.]] | ||
[[Category: Glycoside hydrolase]] | [[Category: Glycoside hydrolase]] | ||
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[[Category: Mannosidase]] | [[Category: Mannosidase]] | ||
[[Category: Transition state mimic]] | [[Category: Transition state mimic]] | ||
| + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Apr 24 09:31:10 2008'' | ||
Revision as of 06:31, 24 April 2008
TRANSITION-STATE MIMICRY IN MANNOSIDE HYDROLYSIS: CHARACTERISATION OF TWENTY SIX INHIBITORS AND INSIGHT INTO BINDING FROM LINEAR FREE ENERGY RELATIONSHIPS AND 3-D STRUCTURE
Overview
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.
About this Structure
2VR4 is a Single protein structure of sequence from Bacteroides thetaiotaomicron. Full crystallographic information is available from OCA.
Reference
Structural and biochemical evidence for a boat-like transition state in beta-mannosidases., Tailford LE, Offen WA, Smith NL, Dumon C, Morland C, Gratien J, Heck MP, Stick RV, Bleriot Y, Vasella A, Gilbert HJ, Davies GJ, Nat Chem Biol. 2008 May;4(5):306-12. PMID:18408714 Page seeded by OCA on Thu Apr 24 09:31:10 2008
Categories: Bacteroides thetaiotaomicron | Beta-mannosidase | Single protein | Bleriot, Y. | Davies, G J. | Dumon, C. | Gilbert, H J. | Gratien, J. | Heck, M P. | Moreland, C. | Offen, W A. | Smith, N L. | Stick, R V. | Tailford, L E. | Vasella, A. | Glycoside hydrolase | Hydrolase | Linear free energy relationship | Mannosidase | Transition state mimic
