View source for 6dyy


==Crystal structure of Helicobacter pylori 5'-methylthioadenosine/S-adenosyl homocysteine nucleosidase (MTAN) complexed with (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(((3-(1-butyl-1H-1,2,3-triazol-4-yl)propyl)thio)methyl)pyrrolidin-3-ol==
<StructureSection load='6dyy' size='340' side='right'caption='[[6dyy]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dyy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Helicobacter_pylori Helicobacter pylori]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DYY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DYY 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]] 1.61&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OS6:(3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-({[3-(1-butyl-1H-1,2,3-triazol-4-yl)propyl]sulfanyl}methyl)pyrrolidin-3-ol'>OS6</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=6dyy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dyy OCA], [https://pdbe.org/6dyy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dyy RCSB], [https://www.ebi.ac.uk/pdbsum/6dyy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dyy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MQMTN_HELPJ MQMTN_HELPJ] Catalyzes the direct conversion of aminodeoxyfutalosine (AFL) into dehypoxanthine futalosine (DHFL) and adenine via the hydrolysis of the N-glycosidic bond; this reaction seems to represent an essential step in the menaquinone biosynthesis pathway in Helicobacter species. Also catalyzes the hydrolysis of 5'-methylthioadenosine (MTA) to adenine and 5'-methylthioribose. Can also probably use S-adenosylhomocysteine (SAH) as substrate, leading to adenine and S-ribosylhomocysteine. These other activities highlight the tremendous versatility of the enzyme, which also plays key roles in S-adenosylmethionine recycling and in the biosynthesis of the quorum-sensing molecule autoinducer-2.<ref>PMID:20954236</ref> <ref>PMID:22891633</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolysis of adenine from S-methyl-5'-thioadenosine (MTA) and S-adenosyl L-homocysteine (SAH) to form S-methyl-5'-thioribose (MTR) and S-ribosyl-L-homocysteine (SRH), respectively. The MTANs are involved in quorum sensing pathways and hydrolyze MTA to metabolites for recycling to S-adenosylmethionine (SAM). A few bacterial species use the futalosine pathway for menaquinone synthesis and in these, MTAN catalyzes an essential step, making it a candidate for species-specific antibiotic development. Helicobacter pylori uses the unusual futalosine pathway for menaquinone biosynthesis and the MTAN from H. pylori (HpMTAN) is a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes phosphorylation reactions with substrate specificity similar to the bacterial MTANs. It plays a metabolic role in the salvage of MTA for SAM salvage pathways and has been reported to be an anticancer target. Transition state analogues designed for HpMTAN and for MTAP have been reported and show significant overlap in specificity. It is desirable to design transition state analogues specific for the HpMTAN as an antibiotic in the treatment of H. pylori infections. Fifteen unique transition state analogues are described here and are used to explore the inhibitor specificity and the structural scaffolds for HpMTAN and MTAP. Several inhibitors are transition-state analogues of H. pylori MTAN with dissociation constants in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. X-ray crystal structures of HpMTAN and MTAP show inhibitors of HpMTAN extending through a hydrophobic channel to the protein surface, while the more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the catalytic site phosphate nucleophile.

"Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase".,Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833<ref>PMID:30860833</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dyy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Helicobacter pylori]]
[[Category: Large Structures]]
[[Category: Almo SC]]
[[Category: Bonanno JB]]
[[Category: Ducati RG]]
[[Category: Harijan RK]]
[[Category: Schramm VL]]