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6DYV

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-((pent-4-yn-1-ylthio)methyl)pyrrolidin-3-ol

Summary for 6DYV
Entry DOI10.2210/pdb6dyv/pdb
Descriptor5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase, 1,2-ETHANEDIOL, (3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-{[(pent-4-yn-1-yl)sulfanyl]methyl}pyrrolidin-3-ol, ... (4 entities in total)
Functional Keywordsmtan enzyme, duodenal ulcers, stomach cancer, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHelicobacter pylori (Campylobacter pylori)
Total number of polymer chains2
Total formula weight55023.29
Authors
Harijan, R.K.,Ducati, R.G.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (deposition date: 2018-07-02, release date: 2019-03-20, Last modification date: 2023-10-11)
Primary citationHarijan, R.K.,Hoff, O.,Ducati, R.G.,Firestone, R.S.,Hirsch, B.M.,Evans, G.B.,Schramm, V.L.,Tyler, P.C.
Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.
J. Med. Chem., 62:3286-3296, 2019
Cited by
PubMed Abstract: Bacterial 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5'-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5'-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.
PubMed: 30860833
DOI: 10.1021/acs.jmedchem.8b01642
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.62 Å)
Structure validation

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