1tmb: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(8 intermediate revisions by the same user not shown)
Line 1: Line 1:
{{STRUCTURE_1tmb|  PDB=1tmb  |  SCENE=  }}
===MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A===
{{ABSTRACT_PUBMED_8367461}}


==Disease==
==MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A==
[[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>
<StructureSection load='1tmb' size='340' side='right'caption='[[1tmb]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1tmb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Theonella_sp. Theonella sp.]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TMB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TMB FirstGlance]. <br>
</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0FL:3-AMINO-N-FORMYL-L-ALANINE'>0FL</scene>, <scene name='pdbligand=0MG:AMINO{[(4S)-4-AMINO-5-CARBOXY-5-OXOPENTYL]AMINO}METHANIMINIUM'>0MG</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=DPN:D-PHENYLALANINE'>DPN</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene>, <scene name='pdbligand=VLT:(2E,4S)-4-AMINO-5-(4-HYDROXYPHENYL)PENT-2-ENOIC+ACID'>VLT</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=1tmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tmb OCA], [https://pdbe.org/1tmb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tmb RCSB], [https://www.ebi.ac.uk/pdbsum/1tmb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tmb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HIRV2_HIRME HIRV2_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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/tm/1tmb_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1tmb ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine sponge Theonella sp., represents an unusual class of serine protease inhibitor. A complex of this inhibitor with human alpha-thrombin, a protease central to the bioregulation of thrombosis and hemostasis, was studied by x-ray crystallography. This work (2.3-A resolution) confirms the structure of CtA and reveals intimate details about its molecular recognition within the enzyme active site. Interactions due to the "Pro-Arg motif" (Arg occupancy of the S1 specificity pocket; formation of a hydrogen-bonded two-strand antiparallel beta-sheet with Ser214-Gly216) and the alpha-keto amide group of CtA are primarily responsible for binding to thrombin, with the alpha-keto amide serving as a transition-state analogue. A special interaction with the "insertion loop" of thrombin (Tyr60A-Thr60I) is manifested through engagement of the hydroxyphenyl group of CtA with Trp60D as part of an "aromatic stacking chain." Biochemical inhibition data (Ki values at 37 degrees C) were obtained for CtA with thrombin and a diverse collection of serine proteases. Thus, CtA is just a moderate inhibitor of human alpha-thrombin (Ki = 0.18 microM) but a potent inhibitor of trypsin (Ki = 0.023 microM) and streptokinase (Ki = 0.035 microM). The relative lack of potency of CtA as a thrombin inhibitor is discussed with respect to certain structural features of the enzyme complex. We also report the total synthesis of CtA, by a convergent [2 + 3] fragment-condensation approach, to serve the preparation of cyclotheonamide analogues for structure-function studies.


==Function==
Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.,Maryanoff BE, Qiu X, Padmanabhan KP, Tulinsky A, Almond HR Jr, Andrade-Gordon P, Greco MN, Kauffman JA, Nicolaou KC, Liu A, et al. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8048-52. PMID:8367461<ref>PMID:8367461</ref>
[[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/HIRV2_HIRME HIRV2_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.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[1tmb]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Theonella_sp. Theonella sp.]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TMB OCA].
</div>
<div class="pdbe-citations 1tmb" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Hirudin|Hirudin]]
*[[Hirudin 3D structures|Hirudin 3D structures]]
*[[Thrombin|Thrombin]]
*[[Thrombin 3D Structures|Thrombin 3D Structures]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:008367461</ref><ref group="xtra">PMID:008732754</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Hirudo medicinalis]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Theonella sp.]]
[[Category: Large Structures]]
[[Category: Thrombin]]
[[Category: Theonella sp]]
[[Category: Maryanoff, B E.]]
[[Category: Maryanoff BE]]
[[Category: Padmanabhan, K P.]]
[[Category: Padmanabhan KP]]
[[Category: Qiu, X.]]
[[Category: Qiu X]]
[[Category: Tulinsky, A.]]
[[Category: Tulinsky A]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Serine proteinase]]

Latest revision as of 11:06, 15 November 2023

MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE AMOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A

Structural highlights

1tmb is a 4 chain structure with sequence from Hirudo medicinalis, Homo sapiens and Theonella sp.. 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

Function

HIRV2_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

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

Publication Abstract from PubMed

The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine sponge Theonella sp., represents an unusual class of serine protease inhibitor. A complex of this inhibitor with human alpha-thrombin, a protease central to the bioregulation of thrombosis and hemostasis, was studied by x-ray crystallography. This work (2.3-A resolution) confirms the structure of CtA and reveals intimate details about its molecular recognition within the enzyme active site. Interactions due to the "Pro-Arg motif" (Arg occupancy of the S1 specificity pocket; formation of a hydrogen-bonded two-strand antiparallel beta-sheet with Ser214-Gly216) and the alpha-keto amide group of CtA are primarily responsible for binding to thrombin, with the alpha-keto amide serving as a transition-state analogue. A special interaction with the "insertion loop" of thrombin (Tyr60A-Thr60I) is manifested through engagement of the hydroxyphenyl group of CtA with Trp60D as part of an "aromatic stacking chain." Biochemical inhibition data (Ki values at 37 degrees C) were obtained for CtA with thrombin and a diverse collection of serine proteases. Thus, CtA is just a moderate inhibitor of human alpha-thrombin (Ki = 0.18 microM) but a potent inhibitor of trypsin (Ki = 0.023 microM) and streptokinase (Ki = 0.035 microM). The relative lack of potency of CtA as a thrombin inhibitor is discussed with respect to certain structural features of the enzyme complex. We also report the total synthesis of CtA, by a convergent [2 + 3] fragment-condensation approach, to serve the preparation of cyclotheonamide analogues for structure-function studies.

Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.,Maryanoff BE, Qiu X, Padmanabhan KP, Tulinsky A, Almond HR Jr, Andrade-Gordon P, Greco MN, Kauffman JA, Nicolaou KC, Liu A, et al. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8048-52. PMID:8367461[1]

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

See Also

References

  1. ↑ Maryanoff BE, Qiu X, Padmanabhan KP, Tulinsky A, Almond HR Jr, Andrade-Gordon P, Greco MN, Kauffman JA, Nicolaou KC, Liu A, et al.. Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8048-52. PMID:8367461

1tmb, resolution 2.30Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=1tmb&oldid=3949727"