2vr4: Difference between revisions
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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== | |||
<StructureSection load='2vr4' size='340' side='right'caption='[[2vr4]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vr4]] 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=2VR4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VR4 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=17B:(2Z,3R,4S,5R,6R)-2-[(4-AMINOBUTYL)IMINO]-6-(HYDROXYMETHYL)PIPERIDINE-3,4,5-TRIOL'>17B</scene>, <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></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=2vr4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vr4 OCA], [https://pdbe.org/2vr4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vr4 RCSB], [https://www.ebi.ac.uk/pdbsum/2vr4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vr4 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/vr/2vr4_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=2vr4 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 2vr4" 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 15:29, 13 December 2023
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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