1q6t: Difference between revisions
New page: left|200px<br /> <applet load="1q6t" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q6t, resolution 2.30Å" /> '''THE STRUCTURE OF PH... |
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[[Image:1q6t.gif|left|200px]]<br /> | [[Image:1q6t.gif|left|200px]]<br /><applet load="1q6t" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1q6t, resolution 2.30Å" /> | caption="1q6t, resolution 2.30Å" /> | ||
'''THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11'''<br /> | '''THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11'''<br /> | ||
==Overview== | ==Overview== | ||
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the | Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1Q6T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG and 600 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | 1Q6T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=600:'>600</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q6T OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Asante-Appiah, E.]] | [[Category: Asante-Appiah, E.]] | ||
[[Category: Bayly, C.]] | [[Category: Bayly, C.]] | ||
[[Category: Becker, J | [[Category: Becker, J W.]] | ||
[[Category: Cromlish, W.]] | [[Category: Cromlish, W.]] | ||
[[Category: Desponts, C.]] | [[Category: Desponts, C.]] | ||
[[Category: Gauthier, J | [[Category: Gauthier, J Y.]] | ||
[[Category: Kennedy, B | [[Category: Kennedy, B P.]] | ||
[[Category: Lau, C | [[Category: Lau, C K.]] | ||
[[Category: Li, C | [[Category: Li, C S.]] | ||
[[Category: Patel, S | [[Category: Patel, S B.]] | ||
[[Category: Ramachandran, C.]] | [[Category: Ramachandran, C.]] | ||
[[Category: Scapin, G.]] | [[Category: Scapin, G.]] | ||
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[[Category: selectivity]] | [[Category: selectivity]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:36:28 2008'' | ||
Revision as of 15:36, 21 February 2008
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THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11
OverviewOverview
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
DiseaseDisease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[176885], Insulin resistance, susceptibility to OMIM:[176885]
About this StructureAbout this Structure
1Q6T is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
ReferenceReference
The structural basis for the selectivity of benzotriazole inhibitors of PTP1B., Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E, Biochemistry. 2003 Oct 7;42(39):11451-9. PMID:14516196
Page seeded by OCA on Thu Feb 21 14:36:28 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Protein-tyrosine-phosphatase
- Single protein
- Asante-Appiah, E.
- Bayly, C.
- Becker, J W.
- Cromlish, W.
- Desponts, C.
- Gauthier, J Y.
- Kennedy, B P.
- Lau, C K.
- Li, C S.
- Patel, S B.
- Ramachandran, C.
- Scapin, G.
- Skorey, K.
- Therien, M.
- Waddleton, D.
- Wang, Q.
- 600
- MG
- Phosphatase
- Secondary binding site
- Selectivity