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| - | [[Image:1lqf.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1lqf| PDB=1lqf | SCENE= }} | | {{STRUCTURE_1lqf| PDB=1lqf | SCENE= }} |
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| - | '''Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor'''
| + | ===Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor=== |
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| - | ==Overview==
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| - | Inhibitors of PTP-1B could be therapeutically beneficial in the treatment of type 2 diabetes. Owing to the large number of phosphatases in the cell, inhibitors against PTP-1B must not only be potent but selective as well. N-Benzoyl-L-glutamyl-[4-phosphono(difluoromethyl)]-L-phenylalanine-[4-phos phono(difluoro-methyl)]-L-phenylalanineamide (BzN-EJJ-amide) is a low nanomolar inhibitor of PTP-1B that shows selectivity over several protein tyrosine phosphatases. To gain an insight into the basis of its potency and selectivity, we evaluated several analogues of the inhibitor and introduced amino acid substitutions into PTP-1B by site-directed mutagenesis. We also determined the crystal structure of PTP-1B in complex with BzN-EJJ-amide at 2.5 A resolution. Our results indicate that the high inhibitory potency is due to interactions of several of its chemical groups with specific protein residues. An interaction between BzN-EJJ-amide and Asp48 is of particular significance, as substitution of Asp48 to alanine resulted in a 100-fold loss in potency. The crystal structure also revealed an unexpected binding orientation for a bisphosphonate inhibitor on PTP-1B, where the second difluorophosphonomethyl phenylalanine (F(2)PMP) moiety is bound close to Arg47 rather than in the previously identified second aryl phosphate site demarked by Arg24 and Arg254. Our results suggest that potent and selective PTP-1B inhibitors may be designed by targeting the region containing Arg47 and Asp48.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12119018}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12119018 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12119018}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Phosphatase]] | | [[Category: Phosphatase]] |
| | [[Category: Phosphonate]] | | [[Category: Phosphonate]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:10:40 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 21:47:47 2008'' |
Revision as of 18:47, 2 July 2008
Template:STRUCTURE 1lqf
Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor
Template:ABSTRACT PUBMED 12119018
About this Structure
1LQF is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates., Asante-Appiah E, Patel S, Dufresne C, Roy P, Wang Q, Patel V, Friesen RW, Ramachandran C, Becker JW, Leblanc Y, Kennedy BP, Scapin G, Biochemistry. 2002 Jul 23;41(29):9043-51. PMID:12119018
Page seeded by OCA on Wed Jul 2 21:47:47 2008
