View source for 6ppy


==Crystal structure of NeuNAc oxime complexed with NeuB, an N-acetylneuraminate synthase from Neisseria meningitidis==
<StructureSection load='6ppy' size='340' side='right'caption='[[6ppy]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ppy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Neisseria_meningitidis_serogroup_B Neisseria meningitidis serogroup B]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PPY 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OVY:(2E,4S,5R,6R,7S,8R)-5-(acetylamino)-4,6,7,8,9-pentahydroxy-2-(hydroxyimino)nonanoic+acid+(non-preferred+name)'>OVY</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=6ppy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ppy OCA], [https://pdbe.org/6ppy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ppy RCSB], [https://www.ebi.ac.uk/pdbsum/6ppy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ppy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/H2VFG5_NEIMI H2VFG5_NEIMI] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
NeuB is a bacterial sialic acid synthase used by neuroinvasive bacteria to synthesize &lt;i&gt;N&lt;/i&gt;-acetylneuraminate (NeuNAc), helping them to evade the host immune system. NeuNAc oxime is a potent slow-binding NeuB inhibitor. It dissociated too slowly to be detected experimentally, with initial estimates of its residence time in the active site being &gt; 47 days. This is longer than the lifetime of a typical bacterial cell, meaning that inhibition is effectively irreversible. Inhibition data fitted well to a model that included a pre-equilibration step with &lt;i&gt;K&lt;/i&gt;&lt;sub&gt;i&lt;/sub&gt; = 36 muM, followed by effectively irreversible conversion to an E*.I complex, with &lt;i&gt;k&lt;/i&gt;&lt;sub&gt;2&lt;\sub&gt; = 5.6 x 10&lt;sup&gt;-5&lt;/sup&gt; s&lt;sup&gt;-1&lt;/sup&gt;. Thus, the inhibitor is able to subvert ligand release and achieve extraordinary residence times in spite of a relatively modest initial dissociation constant. The crystal structure showed the oxime functional group occupying the phosphate binding site normally occupied by the substrate PEP and the tetrahedral intermediate. There was a ~10% residual rate at high inhibitor concentrations regardless of how long NeuB and NeuNAc oxime were pre-incubated together. However, complete inhibition was achieved by incubating NeuNAc oxime with actively catalyzing enzyme. This requirement for the enzyme to be actively turning over in order for the inhibitor to bind to the second subunit demonstrated an important role for inter-subunit communication in the inhibitory mechanism.

NeuNAc oxime: A slow-binding and effectively irreversible inhibitor of the sialic acid synthase NeuB.,Popovic V, Morrison E, Rosanally AZ, Balachandran N, Senson AW, Szabla R, Junop MS, Berti PJ Biochemistry. 2019 Sep 24. doi: 10.1021/acs.biochem.9b00654. PMID:31549502<ref>PMID:31549502</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ppy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Neisseria meningitidis serogroup B]]
[[Category: Berti PJ]]
[[Category: Junop MJ]]
[[Category: Rosanally AZ]]