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| - | [[Image:1tmb.gif|left|200px]] | |
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| - | {{Structure
| + | ==MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A== |
| - | |PDB= 1tmb |SIZE=350|CAPTION= <scene name='initialview01'>1tmb</scene>, resolution 2.3Å
| + | <StructureSection load='1tmb' size='340' side='right'caption='[[1tmb]], [[Resolution|resolution]] 2.30Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=AHT:4-(2,5-DIAMINO-5-HYDROXY-PENTYL)-PHENOL'>AHT</scene>, <scene name='pdbligand=FOR:FORMYL+GROUP'>FOR</scene>, <scene name='pdbligand=SO3:SULFITE+ION'>SO3</scene> | + | <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> |
| - | |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>
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | |GENE=
| + | <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> |
| - | |DOMAIN=
| + | <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> |
| - | |RELATEDENTRY=
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1tmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tmb OCA], [http://www.ebi.ac.uk/pdbsum/1tmb PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1tmb RCSB]</span>
| + | == 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. |
| | | | |
| - | '''MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A'''
| + | 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> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 1tmb" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Overview== | + | ==See Also== |
| - | 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.
| + | *[[Hirudin 3D structures|Hirudin 3D structures]] |
| - | | + | *[[Thrombin 3D Structures|Thrombin 3D Structures]] |
| - | ==About this Structure==
| + | == References == |
| - | 1TMB is a [[Protein complex]] structure of sequences 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=1TMB OCA].
| + | <references/> |
| - | | + | __TOC__ |
| - | ==Reference== | + | </StructureSection> |
| - | 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:[http://www.ncbi.nlm.nih.gov/pubmed/8367461 8367461]
| + | [[Category: Hirudo medicinalis]] |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[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(serine proteinase)]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:58:09 2008''
| + | |
| 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
- ↑ 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
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