1ta2: Difference between revisions

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<StructureSection load='1ta2' size='340' side='right'caption='[[1ta2]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='1ta2' size='340' side='right'caption='[[1ta2]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1ta2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hirme Hirme] and [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TA2 FirstGlance]. <br>
<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>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=176:1-(2-AMINO-3,3-DIPHENYL-PROPIONYL)-PYRROLIDINE-3-CARBOXYLIC+ACID+2,5-DICHLORO-BENZYLAMIDE'>176</scene></td></tr>
</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>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr>
<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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1sl3|1sl3]], [[1ta6|1ta6]]</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>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ta2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ta2 OCA], [http://pdbe.org/1ta2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ta2 RCSB], [http://www.ebi.ac.uk/pdbsum/1ta2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ta2 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN]] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[http://omim.org/entry/613679 613679]]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.<ref>PMID:14962227</ref> <ref>PMID:6405779</ref> <ref>PMID:3771562</ref> <ref>PMID:3567158</ref> <ref>PMID:3801671</ref> <ref>PMID:3242619</ref> <ref>PMID:2719946</ref> <ref>PMID:1354985</ref> <ref>PMID:1421398</ref> <ref>PMID:1349838</ref> <ref>PMID:7865694</ref> <ref>PMID:7792730</ref>  Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[http://omim.org/entry/601367 601367]]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.<ref>PMID:15534175</ref>  Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:[http://omim.org/entry/188050 188050]]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis.  Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:[http://omim.org/entry/614390 614390]]. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.<ref>PMID:11506076</ref> 
== Function ==
[[http://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN]] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.<ref>PMID:2856554</ref>  [[http://www.uniprot.org/uniprot/HIR2_HIRME HIR2_HIRME]] Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ta/1ta2_consurf.spt"</scriptWhenChecked>
     <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/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
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==See Also==
==See Also==
*[[Hirudin|Hirudin]]
*[[Hirudin 3D structures|Hirudin 3D structures]]
*[[Thrombin|Thrombin]]
*[[Thrombin 3D Structures|Thrombin 3D Structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Hirme]]
[[Category: Hirudo medicinalis]]
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[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: Blood clotting]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Thrombin inhibitor complex]]

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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