7uw6: Difference between revisions
m Protected "7uw6" [edit=sysop:move=sysop] |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==The co-crystal structure of low molecular weight protein tyrosine phosphatase (LMW-PTP) with a small molecule inhibitor SPAA-2== | ||
<StructureSection load='7uw6' size='340' side='right'caption='[[7uw6]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7uw6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UW6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UW6 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OIF:2-[(1,3-benzothiazol-2-yl)amino]-2-oxoethane-1-sulfonic+acid'>OIF</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7uw6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uw6 OCA], [https://pdbe.org/7uw6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uw6 RCSB], [https://www.ebi.ac.uk/pdbsum/7uw6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uw6 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PPAC_HUMAN PPAC_HUMAN] Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Protein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% F from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP. | |||
Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors.,He R, Wang J, Yu ZH, Moyers JS, Michael MD, Durham TB, Cramer JW, Qian Y, Lin A, Wu L, Noinaj N, Barrett DG, Zhang ZY J Med Chem. 2022 Oct 5. doi: 10.1021/acs.jmedchem.2c01143. PMID:36197449<ref>PMID:36197449</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7uw6" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Wang J]] | |||
[[Category: Zhang ZY]] | |||
Latest revision as of 20:21, 18 October 2023
The co-crystal structure of low molecular weight protein tyrosine phosphatase (LMW-PTP) with a small molecule inhibitor SPAA-2The co-crystal structure of low molecular weight protein tyrosine phosphatase (LMW-PTP) with a small molecule inhibitor SPAA-2
Structural highlights
FunctionPPAC_HUMAN Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. Publication Abstract from PubMedProtein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% F from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP. Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors.,He R, Wang J, Yu ZH, Moyers JS, Michael MD, Durham TB, Cramer JW, Qian Y, Lin A, Wu L, Noinaj N, Barrett DG, Zhang ZY J Med Chem. 2022 Oct 5. doi: 10.1021/acs.jmedchem.2c01143. PMID:36197449[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||