Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor
The pathogenic bacteria Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to bubonic plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. Because the phosphatase activity of the Yersinia protein tyrosine phosphatase, YopH, is essential for virulence in the Yersinia pathogen, potent and selective YopH inhibitors are expected to serve as novel anti-plague agents. We have identified a specific YopH small molecule inhibitor, p-nitrocatechol sulfate (pNCS), which exhibits a Ki value of 25 microM for YopH and displays a 13-60-fold selectivity in favor of YopH against a panel of mammalian PTPs. To facilitate the understanding of the underlying molecular basis for tight binding and specificity, we have determined the crystal structure of YopH in complex with pNCS at a 2.0-A resolution. The structural data are corroborated by results from kinetic analyses of the interactions of YopH and its site-directed mutants with pNCS. The results show that while the interactions of the sulfuryl moiety and the phenyl ring with the YopH active site contribute to pNCS binding affinity, additional interactions of the hydroxyl and nitro groups in pNCS with Asp-356, Gln-357, Arg-404, and Gln-446 are responsible for the increased potency and selectivity. In particular, we note that residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate in a unique H-bonding network with the hydroxyl group ortho to the sulfuryl moiety, which may be exploited to design more potent and specific YopH inhibitors.
| Medienart: |
Artikel |
|---|
| Erscheinungsjahr: |
2003 |
|---|---|
| Erschienen: |
2003 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:278 |
|---|---|
| Enthalten in: |
The Journal of biological chemistry - 278(2003), 35 vom: 29. Aug., Seite 33392-9 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sun, Jin-Peng [VerfasserIn] |
|---|
| Anmerkungen: |
Date Completed 02.10.2003 Date Revised 06.02.2021 published: Print-Electronic PDB: 1PA9 Citation Status MEDLINE |
|---|
| Förderinstitution / Projekttitel: |
|
|---|
| PPN (Katalog-ID): |
NLM125744277 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM125744277 | ||
| 003 | DE-627 | ||
| 005 | 20231222210355.0 | ||
| 007 | tu | ||
| 008 | 231222s2003 xx ||||| 00| ||eng c | ||
| 028 | 5 | 2 | |a pubmed24n0419.xml |
| 035 | |a (DE-627)NLM125744277 | ||
| 035 | |a (NLM)12810712 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sun, Jin-Peng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor |
| 264 | 1 | |c 2003 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 02.10.2003 | ||
| 500 | |a Date Revised 06.02.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a PDB: 1PA9 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The pathogenic bacteria Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to bubonic plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. Because the phosphatase activity of the Yersinia protein tyrosine phosphatase, YopH, is essential for virulence in the Yersinia pathogen, potent and selective YopH inhibitors are expected to serve as novel anti-plague agents. We have identified a specific YopH small molecule inhibitor, p-nitrocatechol sulfate (pNCS), which exhibits a Ki value of 25 microM for YopH and displays a 13-60-fold selectivity in favor of YopH against a panel of mammalian PTPs. To facilitate the understanding of the underlying molecular basis for tight binding and specificity, we have determined the crystal structure of YopH in complex with pNCS at a 2.0-A resolution. The structural data are corroborated by results from kinetic analyses of the interactions of YopH and its site-directed mutants with pNCS. The results show that while the interactions of the sulfuryl moiety and the phenyl ring with the YopH active site contribute to pNCS binding affinity, additional interactions of the hydroxyl and nitro groups in pNCS with Asp-356, Gln-357, Arg-404, and Gln-446 are responsible for the increased potency and selectivity. In particular, we note that residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate in a unique H-bonding network with the hydroxyl group ortho to the sulfuryl moiety, which may be exploited to design more potent and specific YopH inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Bacterial Outer Membrane Proteins |2 NLM | |
| 650 | 7 | |a Catechols |2 NLM | |
| 650 | 7 | |a Glutamic Acid |2 NLM | |
| 650 | 7 | |a 3KX376GY7L |2 NLM | |
| 650 | 7 | |a Asparagine |2 NLM | |
| 650 | 7 | |a 7006-34-0 |2 NLM | |
| 650 | 7 | |a Arginine |2 NLM | |
| 650 | 7 | |a 94ZLA3W45F |2 NLM | |
| 650 | 7 | |a Protein Tyrosine Phosphatases |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a yopH protein, Yersinia |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a 4-nitrocatechol sulfate |2 NLM | |
| 650 | 7 | |a HD9MHQ536A |2 NLM | |
| 700 | 1 | |a Wu, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Fedorov, Alexander A |e verfasserin |4 aut | |
| 700 | 1 | |a Almo, Steven C |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhong-Yin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of biological chemistry |d 1945 |g 278(2003), 35 vom: 29. Aug., Seite 33392-9 |w (DE-627)NLM000004995 |x 1083-351X |7 nnns |
| 773 | 1 | 8 | |g volume:278 |g year:2003 |g number:35 |g day:29 |g month:08 |g pages:33392-9 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 278 |j 2003 |e 35 |b 29 |c 08 |h 33392-9 | ||