1xuj

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(New page: 200px<br /><applet load="1xuj" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xuj, resolution 1.92&Aring;" /> '''TRYPSIN-KETO-BABIM-Z...)
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[[Image:1xuj.gif|left|200px]]<br /><applet load="1xuj" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1xuj, resolution 1.92&Aring;" />
 
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'''TRYPSIN-KETO-BABIM-ZN+2, PH 8.2'''<br />
 
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==Overview==
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==TRYPSIN-KETO-BABIM-ZN+2, PH 8.2==
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Many serine proteases are targets for therapeutic intervention because, they often play key roles in disease. Small molecule inhibitors of serine, proteases with high affinity are especially interesting as they could be, used as scaffolds from which to develop drugs selective for protease, targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane, (BABIM), standing out as the best inhibitor of trypsin (by a factor of, over 100) in a series of over 60 relatively closely related analogues. By, probing the structural basis of inhibition, we discovered, using, crystallographic methods, a new mode of high-affinity binding in which a, Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of, BABIM and two active site residues, His57 and Ser 195. Zn2+, at, subphysiological levels, enhances inhibition by over 10(3)-fold. The, distinct Zn2+ coordination geometry implies a strong dependence of, affinity on substituents. This unique structural paradigm has enabled, development of potent, highly selective, Zn2+-dependent inhibitors of, several therapeutically important serine proteases, using a, physiologically ubiquitous metal ion.
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<StructureSection load='1xuj' size='340' side='right'caption='[[1xuj]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1xuj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XUJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XUJ 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]] 1.92&#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=BOZ:BIS(5-AMIDINO-BENZIMIDAZOLYL)METHANONE+ZINC'>BOZ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1xuj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xuj OCA], [https://pdbe.org/1xuj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xuj RCSB], [https://www.ebi.ac.uk/pdbsum/1xuj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xuj ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TRY1_BOVIN TRY1_BOVIN]
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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/xu/1xuj_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=1xuj 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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Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.
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==About this Structure==
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Design of potent selective zinc-mediated serine protease inhibitors.,Katz BA, Clark JM, Finer-Moore JS, Jenkins TE, Johnson CR, Ross MJ, Luong C, Moore WR, Stroud RM Nature. 1998 Feb 5;391(6667):608-12. PMID:9468142<ref>PMID:9468142</ref>
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1XUJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with CA, SO4 and BOZ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1XUJ OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Design of potent selective zinc-mediated serine protease inhibitors., Katz BA, Clark JM, Finer-Moore JS, Jenkins TE, Johnson CR, Ross MJ, Luong C, Moore WR, Stroud RM, Nature. 1998 Feb 5;391(6667):608-12. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9468142 9468142]
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</div>
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[[Category: Bos taurus]]
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<div class="pdbe-citations 1xuj" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Trypsin]]
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[[Category: Clark, J.M.]]
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[[Category: Finer-Moore, J.S.]]
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[[Category: Jenkins, T.E.]]
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[[Category: Johnson, C.R.]]
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[[Category: Katz, B.A.]]
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[[Category: Luong, C.]]
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[[Category: Moore, W.R.]]
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[[Category: Rose, M.J.]]
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[[Category: Stroud, R.M.]]
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[[Category: BOZ]]
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[[Category: CA]]
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[[Category: SO4]]
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[[Category: complex]]
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[[Category: designed small molecule ligand with micromolar affinity]]
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[[Category: trypsin-sulfate-small molecule ligand]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 06:21:25 2007''
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==See Also==
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*[[Trypsin 3D structures|Trypsin 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: Bos taurus]]
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[[Category: Large Structures]]
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[[Category: Clark JM]]
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[[Category: Finer-Moore JS]]
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[[Category: Jenkins TE]]
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[[Category: Johnson CR]]
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[[Category: Katz BA]]
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[[Category: Luong C]]
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[[Category: Moore WR]]
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[[Category: Rose MJ]]
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[[Category: Stroud RM]]

Current revision

TRYPSIN-KETO-BABIM-ZN+2, PH 8.2

PDB ID 1xuj

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