Salmonella enterica MTAN at 1.36 Å resolution: A structure-based design of tailored transition state analogs

Antti M. Haapalainen, Keisha Thomas, Peter C. Tyler, Gary B. Evans, Steven C. Almo, Vern L. Schramm

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)963-974
Number of pages12
JournalStructure
Volume21
Issue number6
DOIs
StatePublished - Jun 4 2013

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Pemetrexed
N-Glycosyl Hydrolases
S-Adenosylhomocysteine
Salmonella enterica
Quorum Sensing
adenosylhomocysteine nucleosidase
S-Adenosylmethionine
Aquaporins
Polyamines
Methylation
Bacteria
Enzymes
5'-methylthioadenosine

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Salmonella enterica MTAN at 1.36 Å resolution : A structure-based design of tailored transition state analogs. / Haapalainen, Antti M.; Thomas, Keisha; Tyler, Peter C.; Evans, Gary B.; Almo, Steven C.; Schramm, Vern L.

In: Structure, Vol. 21, No. 6, 04.06.2013, p. 963-974.

Research output: Contribution to journalArticle

Haapalainen, Antti M. ; Thomas, Keisha ; Tyler, Peter C. ; Evans, Gary B. ; Almo, Steven C. ; Schramm, Vern L. / Salmonella enterica MTAN at 1.36 Å resolution : A structure-based design of tailored transition state analogs. In: Structure. 2013 ; Vol. 21, No. 6. pp. 963-974.
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