2ofu
From Proteopedia
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| - | [[Image:2ofu.gif|left|200px]] | + | [[Image:2ofu.gif|left|200px]] |
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| - | '''x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck''' | + | {{Structure |
| + | |PDB= 2ofu |SIZE=350|CAPTION= <scene name='initialview01'>2ofu</scene>, resolution 2.00Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=1N9:2,6-DIMETHYLPHENYL 2-(3,5-DIMETHOXY-4-(3-(4-METHYLPIPERAZIN-1-YL)PROPOXY)PHENYLAMINO)PYRIMIDIN- 4-YL(2,4-DIMETHOXYPHENYL)CARBAMATE'>1N9</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] | ||
| + | |GENE= LCK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2OFU is a [ | + | 2OFU 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=2OFU OCA]. |
==Reference== | ==Reference== | ||
| - | Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity., Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D, Epstein LF, Faust T, Flynn S, Gallant P, Gore A, Gu Y, Hsieh F, Huang X, Lee JH, Metz D, Middleton S, Mohn D, Morgenstern K, Morrison MJ, Novak PM, Oliveira-dos-Santos A, Powers D, Rose P, Schneider S, Sell S, Tudor Y, Turci SM, Welcher AA, White RD, Zack D, Zhao H, Zhu L, Zhu X, Ghiron C, Amouzegh P, Ermann M, Jenkins J, Johnston D, Napier S, Power E, J Med Chem. 2006 Aug 10;49(16):4981-91. PMID:[http:// | + | Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity., Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D, Epstein LF, Faust T, Flynn S, Gallant P, Gore A, Gu Y, Hsieh F, Huang X, Lee JH, Metz D, Middleton S, Mohn D, Morgenstern K, Morrison MJ, Novak PM, Oliveira-dos-Santos A, Powers D, Rose P, Schneider S, Sell S, Tudor Y, Turci SM, Welcher AA, White RD, Zack D, Zhao H, Zhu L, Zhu X, Ghiron C, Amouzegh P, Ermann M, Jenkins J, Johnston D, Napier S, Power E, J Med Chem. 2006 Aug 10;49(16):4981-91. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16884310 16884310] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific protein-tyrosine kinase]] | [[Category: Non-specific protein-tyrosine kinase]] | ||
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[[Category: lck]] | [[Category: lck]] | ||
| - | ''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 17:59:07 2008'' |
Revision as of 15:59, 20 March 2008
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| , resolution 2.00Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | LCK (Homo sapiens) | ||||||
| Activity: | Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck
Contents |
Overview
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)ami no)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
Disease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
About this Structure
2OFU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity., Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D, Epstein LF, Faust T, Flynn S, Gallant P, Gore A, Gu Y, Hsieh F, Huang X, Lee JH, Metz D, Middleton S, Mohn D, Morgenstern K, Morrison MJ, Novak PM, Oliveira-dos-Santos A, Powers D, Rose P, Schneider S, Sell S, Tudor Y, Turci SM, Welcher AA, White RD, Zack D, Zhao H, Zhu L, Zhu X, Ghiron C, Amouzegh P, Ermann M, Jenkins J, Johnston D, Napier S, Power E, J Med Chem. 2006 Aug 10;49(16):4981-91. PMID:16884310
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