4YNB

Crystal structure of Helicobacter pylori 5'-methylthioadenosine/S-adenosyl homocysteine nucleosidase (MTAN) complexed with pyrazinylthio-DADMe-Immucillin-A

Summary for 4YNB

• Entry DOI: 10.2210/pdb4ynb/pdb
• Related: 4FFS 4WKN 4WKO 4WKP
• Descriptor: Aminodeoxyfutalosine nucleosidase, (3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-[(pyrazin-2-ylsulfanyl)methyl]pyrrolidin-3-ol, GLYCEROL, ... (5 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Helicobacter pylori
• Total number of polymer chains: 1
• Total formula weight: 27534.62

Authors

Cameron, S.A.,Wang, S.,Almo, S.C.,Schramm, V.L. (deposition date: 2015-03-09, release date: 2015-11-25, Last modification date: 2023-09-27)

Primary citation

Wang, S.,Cameron, S.A.,Clinch, K.,Evans, G.B.,Wu, Z.,Schramm, V.L.,Tyler, P.C.
New Antibiotic Candidates against Helicobacter pylori.
J.Am.Chem.Soc., 137:14275-14280, 2015

PubMed Abstract: Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram-negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 μg/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000-fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X-ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues.

PubMed: 26494017
DOI: 10.1021/jacs.5b06110

Experimental method

X-RAY DIFFRACTION (2 Å)