1z71
From Proteopedia
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|PDB= 1z71 |SIZE=350|CAPTION= <scene name='initialview01'>1z71</scene>, resolution 1.80Å | |PDB= 1z71 |SIZE=350|CAPTION= <scene name='initialview01'>1z71</scene>, resolution 1.80Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=L17:L17'>L17</scene> | + | |LIGAND= <scene name='pdbligand=L17:L17'>L17</scene>, <scene name='pdbligand=TYS:SULFONATED+TYROSINE'>TYS</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1z71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z71 OCA], [http://www.ebi.ac.uk/pdbsum/1z71 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1z71 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h). | In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h). | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Wong, B.]] | [[Category: Wong, B.]] | ||
[[Category: Yan, Y.]] | [[Category: Yan, Y.]] | ||
| - | [[Category: L17]] | ||
[[Category: thrombin inhibitor complex]] | [[Category: thrombin inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:30:24 2008'' |
Revision as of 22:30, 30 March 2008
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| , resolution 1.80Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
thrombin and P2 pyridine N-oxide inhibitor complex structure
Overview
In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).
About this Structure
1Z71 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold., Nantermet PG, Burgey CS, Robinson KA, Pellicore JM, Newton CL, Deng JZ, Selnick HG, Lewis SD, Lucas BJ, Krueger JA, Miller-Stein C, White RB, Wong B, McMasters DR, Wallace AA, Lynch JJ Jr, Yan Y, Chen Z, Kuo L, Gardell SJ, Shafer JA, Vacca JP, Lyle TA, Bioorg Med Chem Lett. 2005 Jun 2;15(11):2771-5. PMID:15911253
Page seeded by OCA on Mon Mar 31 01:30:24 2008
Categories: Homo sapiens | Protein complex | Thrombin | Burgey, C S. | Chen, Z. | Deng, J Z. | Gardell, S J. | Jr., J J.Lynch. | Krueger, J A. | Kuo, L. | Lewis, S D. | Lucas, B J. | Lyle, T A. | McMasters, D R. | Miller-Stein, C. | Nantermet, P G. | Newton, C L. | Pellicore, J M. | Robinson, K A. | Selnick, H G. | Shafer, J A. | Vacca, J P. | Wallace, A A. | White, R B. | Wong, B. | Yan, Y. | Thrombin inhibitor complex
