4F2P

Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with diEtglycol-thio-DADMe-Immucillin-A

Summary for 4F2P

• Entry DOI: 10.2210/pdb4f2p/pdb
• Related: 4F1W 4F2W
• Descriptor: 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase, (3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-({[2-(2-hydroxyethoxy)ethyl]sulfanyl}methyl)pyrrolidin-3- ol, ACETATE ION, ... (6 entities in total)
• Functional Keywords: l-methionine biosynthetic process from s-adenosylmethionine, l-methionine salvage from methylthioadenosine, 5'-methylthioadenosine/s-adenosylhomocysteine nucleosidase, adenosylhomocysteine nucleosidase activity, methylthioadenosine nucleosidase activity, acting on glycosyl bonds, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Salmonella enterica subsp. enterica serovar Choleraesuis
• Total number of polymer chains: 2
• Total formula weight: 53780.47

Authors

Haapalainen, A.M.,Thomas, K.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (deposition date: 2012-05-08, release date: 2013-05-01, Last modification date: 2024-02-28)

Primary citation

Haapalainen, A.M.,Thomas, K.,Tyler, P.C.,Evans, G.B.,Almo, S.C.,Schramm, V.L.
Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with diEtglycol-thio-DADMe-Immucillin-A
Structure, 21:963-974, 2013

PubMed 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.

PubMed: 23685211
DOI: 10.1016/j.str.2013.04.009

Experimental method

X-RAY DIFFRACTION (1.64 Å)