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| | {{STRUCTURE_2f6f| PDB=2f6f | SCENE= }} | | {{STRUCTURE_2f6f| PDB=2f6f | SCENE= }} |
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| - | '''The structure of the S295F mutant of human PTP1B'''
| + | ===The structure of the S295F mutant of human PTP1B=== |
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| - | ==Overview==
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| - | Regions of protein-tyrosine phosphatase (PTP) 1B that are distant from the active site yet affect inhibitor binding were identified by a novel library screen. This screen was based on the observation that expression of v-Src in yeast leads to lethality, which can be rescued by the coexpression of PTP1B. However, this rescue is lost when yeast are grown in the presence of PTP1B inhibitors. To identify regions of PTP1B (amino acids 1-400, catalytic domain plus 80-amino acid C-terminal tail) that can affect the binding of the difluoromethyl phosphonate (DFMP) inhibitor 7-bromo-6-difluoromethylphosphonate 3-naphthalenenitrile, a library coexpressing PTP1B mutants and v-Src was generated, and the ability of yeast to grow in the presence of the inhibitor was evaluated. PTP1B inhibitor-resistant mutations were found to concentrate on helix alpha7 and its surrounding region, but not in the active site. No resistant amino acid substitutions were found to occur in the C-terminal tail, suggesting that this region has little effect on active-site inhibitor binding. An in-depth characterization of a resistant substitution localizing to region alpha7 (S295F) revealed that this change minimally affected enzyme catalytic activity, but significantly reduced the potency of a panel of structurally diverse DFMP PTP1B inhibitors. This loss of inhibitor potency was found to be due to the difluoro moiety of these inhibitors because only the difluoro inhibitors were shifted. For example, the inhibitor potency of a monofluorinated or non-fluorinated analog of one of these DFMP inhibitors was only minimally affected. Using this type of library screen, which can scan the nearly full-length PTP1B sequence (catalytic domain and C-terminal tail) for effects on inhibitor binding, we have been able to identify novel regions of PTP1B that specifically affect the binding of DFMP inhibitors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16332678}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16332678 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16332678}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Mutation]] | | [[Category: Mutation]] |
| | [[Category: Phosphatase]] | | [[Category: Phosphatase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:31:01 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 06:49:39 2008'' |
Revision as of 03:49, 29 July 2008
Template:STRUCTURE 2f6f
The structure of the S295F mutant of human PTP1B
Template:ABSTRACT PUBMED 16332678
About this Structure
2F6F is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding., Montalibet J, Skorey K, McKay D, Scapin G, Asante-Appiah E, Kennedy BP, J Biol Chem. 2006 Feb 24;281(8):5258-66. Epub 2005 Dec 6. PMID:16332678
Page seeded by OCA on Tue Jul 29 06:49:39 2008
