1ta2: Difference between revisions

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[[Image:1ta2.gif|left|200px]]


{{Structure
==Crystal structure of thrombin in complex with compound 1==
|PDB= 1ta2 |SIZE=350|CAPTION= <scene name='initialview01'>1ta2</scene>, resolution 2.30&Aring;
<StructureSection load='1ta2' size='340' side='right'caption='[[1ta2]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=176:1-(2-AMINO-3,3-DIPHENYL-PROPIONYL)-PYRROLIDINE-3-CARBOXYLIC ACID 2,5-DICHLORO-BENZYLAMIDE'>176</scene>
<table><tr><td colspan='2'>[[1ta2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TA2 FirstGlance]. <br>
|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]  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
|GENE=  
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=176:1-(2-AMINO-3,3-DIPHENYL-PROPIONYL)-PYRROLIDINE-3-CARBOXYLIC+ACID+2,5-DICHLORO-BENZYLAMIDE'>176</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</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=1ta2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ta2 OCA], [https://pdbe.org/1ta2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ta2 RCSB], [https://www.ebi.ac.uk/pdbsum/1ta2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ta2 ProSAT]</span></td></tr>
 
</table>
'''Crystal structure of thrombin in complex with compound 1'''
== Evolutionary Conservation ==
 
[[Image:Consurf_key_small.gif|200px|right]]
 
Check<jmol>
==Overview==
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ta/1ta2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ta2 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.


==Disease==
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.,Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466<ref>PMID:9703466</ref>
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==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1TA2 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=1TA2 OCA].
</div>
<div class="pdbe-citations 1ta2" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position., Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP, J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9703466 9703466]
*[[Hirudin 3D structures|Hirudin 3D structures]]
*[[Thrombin 3D Structures|Thrombin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hirudo medicinalis]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Thrombin]]
[[Category: Baskin EP]]
[[Category: Baskin, E P.]]
[[Category: Brady SF]]
[[Category: Brady, S F.]]
[[Category: Chen I-W]]
[[Category: Chen, I W.]]
[[Category: Cook JJ]]
[[Category: Cook, J J.]]
[[Category: Cooper CM]]
[[Category: Cooper, C M.]]
[[Category: Dancheck KB]]
[[Category: Dancheck, K B.]]
[[Category: Gardel SJ]]
[[Category: Gardel, S J.]]
[[Category: Holahan MA]]
[[Category: Holahan, M A.]]
[[Category: Krueger JA]]
[[Category: Krueger, J A.]]
[[Category: Lewis SD]]
[[Category: Lewis, S D.]]
[[Category: Lucas BY]]
[[Category: Lucas, B Y.]]
[[Category: Lumma WC]]
[[Category: Lumma, W C.]]
[[Category: Lyle EA]]
[[Category: Lyle, E A.]]
[[Category: Lynch JJ]]
[[Category: Lynch, J J.]]
[[Category: Naylor-Olsen AM]]
[[Category: Naylor-Olsen, A M.]]
[[Category: Sisko JT]]
[[Category: Sisko, J T.]]
[[Category: Stauffer KJ]]
[[Category: Stauffer, K J.]]
[[Category: Stranieri MT]]
[[Category: Stranieri, M T.]]
[[Category: Tucker TJ]]
[[Category: Tucker, T J.]]
[[Category: Vacca JP]]
[[Category: Vacca, J P.]]
[[Category: Yan Y]]
[[Category: Yan, Y.]]
[[Category: 176]]
[[Category: thrombin inhibitor complex]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:15:53 2008''

Latest revision as of 03:30, 21 November 2024

Crystal structure of thrombin in complex with compound 1Crystal structure of thrombin in complex with compound 1

Structural highlights

1ta2 is a 2 chain structure with sequence from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.,Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisko JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen IW, Dancheck KB, Krueger JA, Cooper CM, Vacca JP. Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. J Med Chem. 1998 Aug 13;41(17):3210-9. PMID:9703466 doi:http://dx.doi.org/10.1021/jm9801713

1ta2, resolution 2.30Å

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