@article{c9624b13661d4bbea4463cf54b7c6cbb,
title = "Salmonella enterica MTAN at 1.36 {\AA} resolution: A structure-based design of tailored transition state analogs",
abstract = "Accumulation of 5′-methylthioadenosine (MTA) and S- adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines, and production of quorum-sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans and a target for quorum sensing because MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogs of MTA and SAH explain the structural contacts causing pM binding affinity for the inhibitor and reveal a {"}water-wire{"} channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited this discovery by the design and synthesis of tailored modifications of the currently existing transition state analogs to fill this site. This site was not anticipated in MTAN structures. Tailored inhibitors with dissociation constants of 5 to 15 pM are characterized.",
author = "Haapalainen, {Antti M.} and Keisha Thomas and Tyler, {Peter C.} and Evans, {Gary B.} and Almo, {Steven C.} and Schramm, {Vern L.}",
note = "Funding Information: This work was supported by the National Institutes of Health (NIH; GM41916), The New Zealand Foundation for Research, Science, and Technology, and a fellowship from the Sigrid Jus{\'e}lius Foundation (to A.M.H.). Structural data were measured at the beamline X29A at the Case Center for Synchrotron Biosciences (CCSB), located at the National Synchrotron Light Source (NSLS) at Brookhaven National Laboratories (BNL), New York. This publication was made possible by a grant from the Center for Synchrotron Biosciences (P30-EB-009998), from the National Institute of Biomedical Imaging and Bioengineering (NIBIB). Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-98CH10886. Salmonella enterica MTAN is a community-nominated target for the New York Structural Genomics Research Consortium, which is supported by a grant from the NIH (U54 GM094662) (to S.C.A., PI). We acknowledge Drs. Yury Patskovsky and Jeffrey Bonanno for assistance in data collection, data processing, and structural validation. ",
year = "2013",
month = jun,
day = "4",
doi = "10.1016/j.str.2013.04.009",
language = "English (US)",
volume = "21",
pages = "963--974",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "6",
}