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2zfp

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Revision as of 12:03, 29 July 2020

Thrombin Inibition

Structural highlights

2zfp is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Related:	2zc9, 1ypg, 1h8d, 2zda, 2zdv, 2zf0, 2zff
Activity:	Thrombin, with EC number 3.4.21.5
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM: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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM: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.^[13] Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM: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: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.^[14]

Function

[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.^[15] [HIRV1_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.^[16]

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

Successful design of potent and selective protein inhibitors, in terms of structure-based drug design, strongly relies on the correct understanding of the molecular features determining the ligand binding to the target protein. We present a case study of serine protease inhibitors with a bis(phenyl)methane moiety binding into the S3 pocket. These inhibitors bind with remarkable potency to the active site of thrombin, the blood coagulation factor IIa. A combination of X-ray crystallography and isothermal titration calorimetry provides conclusive insights into the driving forces responsible for the surprisingly high potency of these inhibitors. Analysis of six well-resolved crystal structures (resolution 1.58-2.25 A) along with the thermodynamic data allows an explanation of the tight binding of the bis(phenyl)methane inhibitors. Interestingly, the two phenyl rings contribute to binding affinity for very different reasons - a fact that can only be elucidated by a structure-based approach. The first phenyl moiety occupies the hydrophobic S3 pocket, resulting in a mainly entropic advantage of binding. This observation is based on the displacement of structural water molecules from the S3 pocket that are observed in complexes with inhibitors that do not bind in the S3 pocket. The same classic hydrophobic effect cannot explain the enhanced binding affinity resulting from the attachment of the second, more solvent-exposed phenyl ring. For the bis(phenyl)methane inhibitors, an observed adaptive rotation of a glutamate residue adjacent to the S3 binding pocket attracted our attention. The rotation of this glutamate into salt-bridging distance with a lysine moiety correlates with an enhanced enthalpic contribution to binding for these highly potent thrombin binders. This explanation for the magnitude of the attractive force is confirmed by data retrieved by a Relibase search of several thrombin-inhibitor complexes deposited in the Protein Data Bank exhibiting similar molecular features. Special attention was attributed to putative changes in the protonation states of the interaction partners. For this purpose, two analogous inhibitors differing mainly in their potential to change the protonation state of a hydrogen-bond donor functionality were compared. Buffer dependencies of the binding enthalpy associated with complex formation could be traced by isothermal titration calorimetry, which revealed, along with analysis of the crystal structures (resolution 1.60 and 1.75 A), that a virtually compensating proton interchange between enzyme, inhibitor and buffer is responsible for the observed buffer-independent thermodynamic signatures.

Think twice: understanding the high potency of bis(phenyl)methane inhibitors of thrombin.,Baum B, Muley L, Heine A, Smolinski M, Hangauer D, Klebe G J Mol Biol. 2009 Aug 21;391(3):552-64. Epub 2009 Jun 9. PMID:19520086^[17]

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

References

↑ Wang W, Fu Q, Zhou R, Wu W, Ding Q, Hu Y, Wang X, Wang H, Wang Z. Prothrombin Shanghai: hypoprothrombinaemia caused by substitution of Gla29 by Gly. Haemophilia. 2004 Jan;10(1):94-7. PMID:14962227
↑ Board PG, Shaw DC. Determination of the amino acid substitution in human prothrombin type 3 (157 Glu leads to Lys) and the localization of a third thrombin cleavage site. Br J Haematol. 1983 Jun;54(2):245-54. PMID:6405779
↑ Rabiet MJ, Furie BC, Furie B. Molecular defect of prothrombin Barcelona. Substitution of cysteine for arginine at residue 273. J Biol Chem. 1986 Nov 15;261(32):15045-8. PMID:3771562
↑ Miyata T, Morita T, Inomoto T, Kawauchi S, Shirakami A, Iwanaga S. Prothrombin Tokushima, a replacement of arginine-418 by tryptophan that impairs the fibrinogen clotting activity of derived thrombin Tokushima. Biochemistry. 1987 Feb 24;26(4):1117-22. PMID:3567158
↑ Inomoto T, Shirakami A, Kawauchi S, Shigekiyo T, Saito S, Miyoshi K, Morita T, Iwanaga S. Prothrombin Tokushima: characterization of dysfunctional thrombin derived from a variant of human prothrombin. Blood. 1987 Feb;69(2):565-9. PMID:3801671
↑ Henriksen RA, Mann KG. Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382. Biochemistry. 1988 Dec 27;27(26):9160-5. PMID:3242619
↑ Henriksen RA, Mann KG. Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity. Biochemistry. 1989 Mar 7;28(5):2078-82. PMID:2719946
↑ Miyata T, Aruga R, Umeyama H, Bezeaud A, Guillin MC, Iwanaga S. Prothrombin Salakta: substitution of glutamic acid-466 by alanine reduces the fibrinogen clotting activity and the esterase activity. Biochemistry. 1992 Aug 25;31(33):7457-62. PMID:1354985
↑ Morishita E, Saito M, Kumabashiri I, Asakura H, Matsuda T, Yamaguchi K. Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (Met-337-->Thr and Arg-388-->His). Blood. 1992 Nov 1;80(9):2275-80. PMID:1421398
↑ Iwahana H, Yoshimoto K, Shigekiyo T, Shirakami A, Saito S, Itakura M. Detection of a single base substitution of the gene for prothrombin Tokushima. The application of PCR-SSCP for the genetic and molecular analysis of dysprothrombinemia. Int J Hematol. 1992 Feb;55(1):93-100. PMID:1349838
↑ James HL, Kim DJ, Zheng DQ, Girolami A. Prothrombin Padua I: incomplete activation due to an amino acid substitution at a factor Xa cleavage site. Blood Coagul Fibrinolysis. 1994 Oct;5(5):841-4. PMID:7865694
↑ Degen SJ, McDowell SA, Sparks LM, Scharrer I. Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala. Thromb Haemost. 1995 Feb;73(2):203-9. PMID:7792730
↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
↑ Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol. 2001 Aug;46(2):124-31. PMID:11506076
↑ Glenn KC, Frost GH, Bergmann JS, Carney DH. Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis. Pept Res. 1988 Nov-Dec;1(2):65-73. PMID:2856554
↑ Song X, Mo W, Liu X, Zhu L, Yan X, Song H, Dai L. The NMR solution structure of recombinant RGD-hirudin. Biochem Biophys Res Commun. 2007 Aug 17;360(1):103-8. Epub 2007 Jun 13. PMID:17585879 doi:10.1016/j.bbrc.2007.06.014
↑ Baum B, Muley L, Heine A, Smolinski M, Hangauer D, Klebe G. Think twice: understanding the high potency of bis(phenyl)methane inhibitors of thrombin. J Mol Biol. 2009 Aug 21;391(3):552-64. Epub 2009 Jun 9. PMID:19520086 doi:10.1016/j.jmb.2009.06.016

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zfp"

@@ Line 1: / Line 1: @@
 ==Thrombin Inibition==
-<StructureSection load='2zfp' size='340' side='right' caption='[[2zfp]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
+<StructureSection load='2zfp' size='340' side='right'caption='[[2zfp]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2zfp]] is a 3 chain structure with 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=2ZFP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZFP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2zfp]] is a 3 chain structure with 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=2ZFP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2ZFP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19U:1-[(2R)-2-AMINOBUTANOYL]-N-(3-CHLOROBENZYL)-L-PROLINAMIDE'>19U</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19U:1-[(2R)-2-AMINOBUTANOYL]-N-(3-CHLOROBENZYL)-L-PROLINAMIDE'>19U</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2zc9|2zc9]], [[1ypg|1ypg]], [[1h8d|1h8d]], [[2zda|2zda]], [[2zdv|2zdv]], [[2zf0|2zf0]], [[2zff|2zff]]</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=2zfp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zfp OCA], [http://pdbe.org/2zfp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zfp RCSB], [http://www.ebi.ac.uk/pdbsum/2zfp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zfp ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2zfp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zfp OCA], [http://pdbe.org/2zfp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zfp RCSB], [http://www.ebi.ac.uk/pdbsum/2zfp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zfp ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 35: / Line 35: @@
 ==See Also==
-*[[Hirudin|Hirudin]]
+*[[Hirudin 3D structures|Hirudin 3D structures]]
-*[[Thrombin|Thrombin]]
+*[[Thrombin 3D Structures|Thrombin 3D Structures]]
 == References ==
 <references/>
@@ Line 42: / Line 42: @@
 </StructureSection>
 [[Category: Homo sapiens]]
+[[Category: Large Structures]]
 [[Category: Thrombin]]
 [[Category: Baum, B]]

2zfp

From Proteopedia

Revision as of 12:03, 29 July 2020

Thrombin Inibition

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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