Salmonella enterica MTAN at 1.36 Å resolution : a structure-based design of tailored transition state analogs
Copyright © 2013 Elsevier Ltd. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Structure (London, England : 1993) - 21(2013), 6 vom: 04. Juni, Seite 963-74 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Haapalainen, Antti M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.01.2014 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.str.2013.04.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM227604911 |
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| 100 | 1 | |a Haapalainen, Antti M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Salmonella enterica MTAN at 1.36 Å resolution |b a structure-based design of tailored transition state analogs |
| 264 | 1 | |c 2013 | |
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| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2013 Elsevier Ltd. All rights reserved. | ||
| 520 | |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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Deoxyadenosines |2 NLM | |
| 650 | 7 | |a Polymers |2 NLM | |
| 650 | 7 | |a Propylene Glycols |2 NLM | |
| 650 | 7 | |a Thionucleosides |2 NLM | |
| 650 | 7 | |a polypropylene glycol |2 NLM | |
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| 650 | 7 | |a 5'-methylthioadenosine |2 NLM | |
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| 650 | 7 | |a S-Adenosylhomocysteine |2 NLM | |
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| 700 | 1 | |a Thomas, Keisha |e verfasserin |4 aut | |
| 700 | 1 | |a Tyler, Peter C |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Gary B |e verfasserin |4 aut | |
| 700 | 1 | |a Almo, Steven C |e verfasserin |4 aut | |
| 700 | 1 | |a Schramm, Vern L |e verfasserin |4 aut | |
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