View source for 5m17


==Structure of the GH99 endo-alpha-mannanase from Bacteroides xylanisolvens in complex with mannose-alpha-1,3-1,2-dideoxymannose==
<StructureSection load='5m17' size='340' side='right'caption='[[5m17]], [[Resolution|resolution]] 1.03&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5m17]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacteroides_xylanisolvens_XB1A Bacteroides xylanisolvens XB1A]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M17 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]] 1.03&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7D1:(2~{R},3~{S},4~{R})-2-(HYDROXYMETHYL)OXANE-3,4-DIOL'>7D1</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</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=5m17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m17 OCA], [https://pdbe.org/5m17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m17 RCSB], [https://www.ebi.ac.uk/pdbsum/5m17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m17 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/D6D1V7_9BACE D6D1V7_9BACE] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibitor design incorporating features of the reaction coordinate and transition-state structure has emerged as a powerful approach for the development of enzyme inhibitors. Such inhibitors find use as mechanistic probes, chemical biology tools, and therapeutics. Endo-alpha-1,2-mannosidases and endo-alpha-1,2-mannanases, members of glycoside hydrolase family 99 (GH99), are interesting targets for inhibitor development as they play key roles in N-glycan maturation and microbiotal yeast mannan degradation, respectively. These enzymes are proposed to act via a 1,2-anhydrosugar "epoxide" mechanism that proceeds through an unusual conformational itinerary. Here, we explore how shape and charge contribute to binding of diverse inhibitors of these enzymes. We report the synthesis of neutral dideoxy, glucal and cyclohexenyl disaccharide inhibitors, their binding to GH99 endo-alpha-1,2-mannanases, and their structural analysis by X-ray crystallography. Quantum mechanical calculations of the free energy landscapes reveal how the neutral inhibitors provide shape but not charge mimicry of the proposed intermediate and transition state structures. Building upon the knowledge of shape and charge contributions to inhibition of family GH99 enzymes, we design and synthesize alpha-Man-1,3-noeuromycin, which is revealed to be the most potent inhibitor (KD 13 nM for Bacteroides xylanisolvens GH99 enzyme) of these enzymes yet reported. This work reveals how shape and charge mimicry of transition state features can enable the rational design of potent inhibitors.

Contribution of Shape and Charge to the Inhibition of a Family GH99 endo-alpha-1,2-Mannanase.,Petricevic M, Sobala LF, Fernandes PZ, Raich L, Thompson AJ, Bernardo-Seisdedos G, Millet O, Zhu S, Sollogoub M, Jimenez-Barbero J, Rovira C, Davies GJ, Williams SJ J Am Chem Soc. 2017 Jan 17. doi: 10.1021/jacs.6b10075. PMID:27992199<ref>PMID:27992199</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5m17" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bacteroides xylanisolvens XB1A]]
[[Category: Large Structures]]
[[Category: Bernardo-Seisdedos G]]
[[Category: Davies GJ]]
[[Category: Fernandes PZ]]
[[Category: Jimenez-Barbero J]]
[[Category: Millet O]]
[[Category: Petricevic M]]
[[Category: Raich L]]
[[Category: Rovira C]]
[[Category: Sobala LF]]
[[Category: Sollogoub M]]
[[Category: Thompson AJ]]
[[Category: Williams SJ]]
[[Category: Zhu S]]