1q6t: Difference between revisions

Revision as of 05:56, 3 May 2008

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.

About this StructureAbout this Structure

1Q6T is a Single protein structure of sequence from Homo sapiens. 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 Sat May 3 05:56:21 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:1q6t.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1q6t |SIZE=350|CAPTION= <scene name='initialview01'>1q6t</scene>, resolution 2.30&Aring;
+The line below this paragraph, containing "STRUCTURE_1q6t", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=600:6-[4-((2S)-2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-3-{4-[DIFLUORO(PHOSPHONO)METHYL]PHENYL}-2-PHENYLPROPYL)PHENYL]-2-[(1S)-1-METHOXY-3-METHYLBUTYL]QUINOLIN-8-YLPHOSPHONIC+ACID'>600</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= PTPN1 OR PTP1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_1q6t|  PDB=1q6t  |  SCENE=  }}
-|RELATEDENTRY=[[1q6j|1Q6J]], [[1q6m|1Q6M]], [[1q6n|1Q6N]], [[1q6p|1Q6P]], [[1q6s|1Q6S]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1q6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q6t OCA], [http://www.ebi.ac.uk/pdbsum/1q6t PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1q6t RCSB]</span>
-}}
 '''THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11'''
@@ Line 42: / Line 39: @@
 [[Category: Waddleton, D.]]
 [[Category: Wang, Q.]]
-[[Category: phosphatase]]
+[[Category: Phosphatase]]
-[[Category: secondary binding site]]
+[[Category: Secondary binding site]]
-[[Category: selectivity]]
+[[Category: Selectivity]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 05:56:21 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:09:35 2008''