1z71
From Proteopedia
(New page: 200px<br /> <applet load="1z71" size="450" color="white" frame="true" align="right" spinBox="true" caption="1z71, resolution 1.80Å" /> '''thrombin and P2 pyr...) |
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| - | [[Image:1z71.gif|left|200px]]<br /> | + | [[Image:1z71.gif|left|200px]]<br /><applet load="1z71" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1z71" size=" | + | |
caption="1z71, resolution 1.80Å" /> | caption="1z71, resolution 1.80Å" /> | ||
'''thrombin and P2 pyridine N-oxide inhibitor complex structure'''<br /> | '''thrombin and P2 pyridine N-oxide inhibitor complex structure'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In this study, we have demonstrated that the critical hydrogen bonding | + | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1Z71 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with L17 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | + | 1Z71 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=L17:'>L17</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z71 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Thrombin]] | [[Category: Thrombin]] | ||
| - | [[Category: Burgey, C | + | [[Category: Burgey, C S.]] |
[[Category: Chen, Z.]] | [[Category: Chen, Z.]] | ||
| - | [[Category: Deng, J | + | [[Category: Deng, J Z.]] |
| - | [[Category: Gardell, S | + | [[Category: Gardell, S J.]] |
| - | [[Category: Jr., J | + | [[Category: Jr., J J.Lynch.]] |
| - | [[Category: Krueger, J | + | [[Category: Krueger, J A.]] |
[[Category: Kuo, L.]] | [[Category: Kuo, L.]] | ||
| - | [[Category: Lewis, S | + | [[Category: Lewis, S D.]] |
| - | [[Category: Lucas, B | + | [[Category: Lucas, B J.]] |
| - | [[Category: Lyle, T | + | [[Category: Lyle, T A.]] |
| - | [[Category: McMasters, D | + | [[Category: McMasters, D R.]] |
[[Category: Miller-Stein, C.]] | [[Category: Miller-Stein, C.]] | ||
| - | [[Category: Nantermet, P | + | [[Category: Nantermet, P G.]] |
| - | [[Category: Newton, C | + | [[Category: Newton, C L.]] |
| - | [[Category: Pellicore, J | + | [[Category: Pellicore, J M.]] |
| - | [[Category: Robinson, K | + | [[Category: Robinson, K A.]] |
| - | [[Category: Selnick, H | + | [[Category: Selnick, H G.]] |
| - | [[Category: Shafer, J | + | [[Category: Shafer, J A.]] |
| - | [[Category: Vacca, J | + | [[Category: Vacca, J P.]] |
| - | [[Category: Wallace, A | + | [[Category: Wallace, A A.]] |
| - | [[Category: White, R | + | [[Category: White, R B.]] |
[[Category: Wong, B.]] | [[Category: Wong, B.]] | ||
[[Category: Yan, Y.]] | [[Category: Yan, Y.]] | ||
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[[Category: thrombin inhibitor complex]] | [[Category: thrombin inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:12:42 2008'' |
Revision as of 14:12, 21 February 2008
|
thrombin and P2 pyridine N-oxide inhibitor complex structure
Contents |
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).
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1Z71 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Thrombin, with EC number 3.4.21.5 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 Thu Feb 21 16:12:42 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. | L17 | Thrombin inhibitor complex
