2vmf: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| (10 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Structural and biochemical evidence for a boat-like transition state in beta-mannosidases== | |||
<StructureSection load='2vmf' size='340' side='right'caption='[[2vmf]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vmf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacteroides_thetaiotaomicron_VPI-5482 Bacteroides thetaiotaomicron VPI-5482]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VMF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VMF FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MVL:(5R,6R,7S,8R)-5-(HYDROXYMETHYL)-5,6,7,8-TETRAHYDROIMIDAZO[1,2-A]PYRIDINE-6,7,8-TRIOL'>MVL</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vmf OCA], [https://pdbe.org/2vmf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vmf RCSB], [https://www.ebi.ac.uk/pdbsum/2vmf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vmf ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8AAK6_BACTN Q8AAK6_BACTN] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vm/2vmf_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vmf ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:18408714</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2vmf" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Mannosidase 3D structures|Mannosidase 3D structures]] | |||
[[Category: Bacteroides thetaiotaomicron | == References == | ||
<references/> | |||
[[Category: | __TOC__ | ||
[[Category: Bleriot | </StructureSection> | ||
[[Category: Davies | [[Category: Bacteroides thetaiotaomicron VPI-5482]] | ||
[[Category: Dumon | [[Category: Large Structures]] | ||
[[Category: Gilbert | [[Category: Bleriot Y]] | ||
[[Category: Gratien | [[Category: Davies GJ]] | ||
[[Category: Heck | [[Category: Dumon C]] | ||
[[Category: Moreland | [[Category: Gilbert HJ]] | ||
[[Category: Offen | [[Category: Gratien J]] | ||
[[Category: Smith | [[Category: Heck MP]] | ||
[[Category: Stick | [[Category: Moreland C]] | ||
[[Category: Tailford | [[Category: Offen WA]] | ||
[[Category: Vasella | [[Category: Smith NL]] | ||
[[Category: Stick RV]] | |||
[[Category: Tailford LE]] | |||
[[Category: Vasella A]] | |||
Latest revision as of 18:25, 13 December 2023
Structural and biochemical evidence for a boat-like transition state in beta-mannosidasesStructural and biochemical evidence for a boat-like transition state in beta-mannosidases
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEnzyme 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||