1lqf
From Proteopedia
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| - | [[Image:1lqf.jpg|left|200px]] | + | [[Image:1lqf.jpg|left|200px]] |
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| - | '''Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor''' | + | {{Structure |
| + | |PDB= 1lqf |SIZE=350|CAPTION= <scene name='initialview01'>1lqf</scene>, resolution 2.5Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=BGD:N-BENZOYL-L-GLUTAMYL-[4-PHOSPHONO(DIFLUOROMETHYL)]-L-PHENYLALANINE-[4-PHOSPHONO(DIFLUORO-METHYL)]-L-PHENYLALANINEAMIDE'>BGD</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1LQF is a [ | + | 1LQF is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LQF OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/12119018 12119018] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein-tyrosine-phosphatase]] | [[Category: Protein-tyrosine-phosphatase]] | ||
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[[Category: inhibitor]] | [[Category: inhibitor]] | ||
[[Category: phosphatase]] | [[Category: phosphatase]] | ||
| - | [[Category: | + | [[Category: phosphonate]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:33:56 2008'' |
Revision as of 10:33, 20 March 2008
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| , resolution 2.5Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | Protein-tyrosine-phosphatase, with EC number 3.1.3.48 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of PTP1b in Complex with a Peptidic Bisphosphonate Inhibitor
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
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
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