1o2g

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[[Image:1o2g.jpg|left|200px]]<br /><applet load="1o2g" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1o2g, resolution 1.58&Aring;" />
 
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'''Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors'''<br />
 
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==Overview==
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==Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors==
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An extensive structural manifold of short hydrogen bond-mediated, active, site-directed, serine protease inhibition motifs is revealed in a set of, over 300 crystal structures involving a large suite of small molecule, inhibitors (2-(2-phenol)-indoles and 2-(2-phenol)-benzimidazoles), determined over a wide range of pH (3.5-11.4). The active site, hydrogen-bonding mode was found to vary markedly with pH, with the steric, and electronic properties of the inhibitor, and with the type of protease, (trypsin, thrombin or urokinase type plasminogen activator (uPA)). The pH, dependence of the active site hydrogen-bonding motif is often intricate, constituting a distinct fingerprint of each complex. Isosteric, replacements or minor substitutions within the inhibitor that modulate the, pK(a) of the phenol hydroxyl involved in short hydrogen bonding, or that, affect steric interactions distal to the active site, can significantly, shift the pH-dependent structural profile characteristic of the parent, scaffold, or produce active site-binding motifs unique to the bound, analog.Ionization equilibria at the active site associated with inhibitor, binding are probed in a series of the protease-inhibitor complexes through, analysis of the pH dependence of the structure and environment of the, active site-binding groups involved in short hydrogen bond arrays., Structures determined at high pH (&gt;11), suggest that the pK(a) of His57 is, dramatically elevated, to a value as high as approximately 11 in certain, complexes. K(i) values involving uPA and trypsin determined as a function, of pH for a set of inhibitors show pronounced parabolic pH dependence, the, pH for optimal inhibition governed by the pK(a) of the inhibitor phenol, involved in short hydrogen bonds. Comparison of structures of trypsin, thrombin and uPA, each bound by the same inhibitor, highlights important, structural variations in the S1 and active sites accessible for, engineering notable selectivity into remarkably small molecules with low, nanomolar K(i) values.
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<StructureSection load='1o2g' size='340' side='right'caption='[[1o2g]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1o2g]] is a 3 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=1O2G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1O2G FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=696:3-{5-[AMINO(IMINIO)METHYL]-1H-INDOL-2-YL}-1,1-BIPHENYL-2-OLATE'>696</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1o2g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1o2g OCA], [https://pdbe.org/1o2g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1o2g RCSB], [https://www.ebi.ac.uk/pdbsum/1o2g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1o2g ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[https://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:[https://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:[https://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:[https://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>
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== Function ==
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[https://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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o2/1o2g_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1o2g ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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An extensive structural manifold of short hydrogen bond-mediated, active site-directed, serine protease inhibition motifs is revealed in a set of over 300 crystal structures involving a large suite of small molecule inhibitors (2-(2-phenol)-indoles and 2-(2-phenol)-benzimidazoles) determined over a wide range of pH (3.5-11.4). The active site hydrogen-bonding mode was found to vary markedly with pH, with the steric and electronic properties of the inhibitor, and with the type of protease (trypsin, thrombin or urokinase type plasminogen activator (uPA)). The pH dependence of the active site hydrogen-bonding motif is often intricate, constituting a distinct fingerprint of each complex. Isosteric replacements or minor substitutions within the inhibitor that modulate the pK(a) of the phenol hydroxyl involved in short hydrogen bonding, or that affect steric interactions distal to the active site, can significantly shift the pH-dependent structural profile characteristic of the parent scaffold, or produce active site-binding motifs unique to the bound analog.Ionization equilibria at the active site associated with inhibitor binding are probed in a series of the protease-inhibitor complexes through analysis of the pH dependence of the structure and environment of the active site-binding groups involved in short hydrogen bond arrays. Structures determined at high pH (&gt;11), suggest that the pK(a) of His57 is dramatically elevated, to a value as high as approximately 11 in certain complexes. K(i) values involving uPA and trypsin determined as a function of pH for a set of inhibitors show pronounced parabolic pH dependence, the pH for optimal inhibition governed by the pK(a) of the inhibitor phenol involved in short hydrogen bonds. Comparison of structures of trypsin, thrombin and uPA, each bound by the same inhibitor, highlights important structural variations in the S1 and active sites accessible for engineering notable selectivity into remarkably small molecules with low nanomolar K(i) values.
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==Disease==
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Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors.,Katz BA, Elrod K, Verner E, Mackman RL, Luong C, Shrader WD, Sendzik M, Spencer JR, Sprengeler PA, Kolesnikov A, Tai VW, Hui HC, Breitenbucher JG, Allen D, Janc JW J Mol Biol. 2003 May 23;329(1):93-120. PMID:12742021<ref>PMID:12742021</ref>
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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]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1O2G is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene> and <scene name='pdbligand=696:'>696</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1O2G OCA].
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</div>
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<div class="pdbe-citations 1o2g" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors., Katz BA, Elrod K, Verner E, Mackman RL, Luong C, Shrader WD, Sendzik M, Spencer JR, Sprengeler PA, Kolesnikov A, Tai VW, Hui HC, Breitenbucher JG, Allen D, Janc JW, J Mol Biol. 2003 May 23;329(1):93-120. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12742021 12742021]
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*[[Hirudin 3D structures|Hirudin 3D structures]]
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*[[Thrombin 3D Structures|Thrombin 3D Structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Hirudo medicinalis]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Thrombin]]
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[[Category: Allen D]]
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[[Category: Allen, D.]]
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[[Category: Breitenbucher G]]
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[[Category: Breitenbucher, G.]]
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[[Category: Elrod K]]
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[[Category: Elrod, K.]]
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[[Category: Hui H]]
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[[Category: Hui, H.]]
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[[Category: Janc J]]
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[[Category: Janc, J.]]
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[[Category: Katz BA]]
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[[Category: Katz, B.A.]]
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[[Category: Kolesnikov A]]
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[[Category: Kolesnikov, A.]]
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[[Category: Luong C]]
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[[Category: Luong, C.]]
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[[Category: Mackman RL]]
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[[Category: Mackman, R.L.]]
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[[Category: Sendzik M]]
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[[Category: Sendzik, M.]]
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[[Category: Shrader W]]
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[[Category: Shrader, W.]]
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[[Category: Spencer JR]]
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[[Category: Spencer, J.R.]]
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[[Category: Sprengeler PA]]
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[[Category: Sprengeler, P.A.]]
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[[Category: Tai WF]]
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[[Category: Tai, W.F.]]
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[[Category: Verner E]]
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[[Category: Verner, E.]]
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[[Category: 696]]
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[[Category: NA]]
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[[Category: factor xa]]
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[[Category: inhibition mechanism]]
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[[Category: serine protease]]
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[[Category: shift of pka]]
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[[Category: short hydrogen bond]]
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[[Category: thrombin]]
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[[Category: trypsin]]
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[[Category: urokinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:31:58 2008''
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Current revision

Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors

PDB ID 1o2g

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