4F3C: Crystal Structure of 5'-methylthioadenosine/s-adenosylhomocysteine Nucleosidase From Salmonella Enterica With Butyl-thio-dadme- Immucillin-a

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.
PDB ID: 4F3CDownload
MMDB ID: 109588
PDB Deposition Date: 2012/5/9
Updated in MMDB: 2013/06 
Experimental Method:
x-ray diffraction
Resolution: 1.93  Å
Source Organism:
Similar Structures:
Biological Unit for 4F3C: dimeric; determined by author and by software (PISA)
Molecular Components in 4F3C
Label Count Molecule
Proteins (2 molecules)
5'-methylthioadenosine/s-adenosylhomocysteine Nucleosidase
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB