2hu6: Difference between revisions

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-[[Image:2hu6.jpg|left|200px]]
- {{Structure
+==Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor==
-|PDB= 2hu6 |SIZE=350|CAPTION= <scene name='initialview01'>2hu6</scene>, resolution 1.32&Aring;
+<StructureSection load='2hu6' size='340' side='right'caption='[[2hu6]], [[Resolution|resolution]] 1.32&Aring;' scene=''>
-|SITE=
+== Structural highlights ==
-|LIGAND= <scene name='pdbligand=37A:(1S,5S,7R)-N~7~-(BIPHENYL-4-YLMETHYL)-N~3~-HYDROXY-6,8-DIOXA-3-AZABICYCLO[3.2.1]OCTANE-3,7-DICARBOXAMIDE'>37A</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
+<table><tr><td colspan='2'>[[2hu6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HU6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HU6 FirstGlance]. <br>
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Macrophage_elastase Macrophage elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.65 3.4.24.65] </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]] 1.32&#8491;</td></tr>
-|GENE= MMP12, HME ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=37A:(1S,5S,7R)-N~7~-(BIPHENYL-4-YLMETHYL)-N~3~-HYDROXY-6,8-DIOXA-3-AZABICYCLO[3.2.1]OCTANE-3,7-DICARBOXAMIDE'>37A</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2hu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hu6 OCA], [https://pdbe.org/2hu6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hu6 RCSB], [https://www.ebi.ac.uk/pdbsum/2hu6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hu6 ProSAT]</span></td></tr>
-|RELATEDENTRY=[[1y93|1Y93]], [[1rmz|1RMZ]]
+</table>
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hu6 OCA], [http://www.ebi.ac.uk/pdbsum/2hu6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2hu6 RCSB]</span>
+== Function ==
-}}
+[https://www.uniprot.org/uniprot/MMP12_HUMAN MMP12_HUMAN] May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
+== 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/hu/2hu6_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=2hu6 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).
-'''Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor'''
+Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.,Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:16899369<ref>PMID:16899369</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2hu6" style="background-color:#fffaf0;"></div>
-==Overview==
+==See Also==
-Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).
+*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-HU6 is a [[Single protein]] structure of 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=2HU6 OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors., Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A, Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16899369 16899369]
 [[Category: Homo sapiens]]
-[[Category: Macrophage elastase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Calderone V]]
-[[Category: Calderone, V.]]
+[[Category: Fragai M]]
-[[Category: Fragai, M.]]
+[[Category: Guarna A]]
-[[Category: Guarna, A.]]
+[[Category: Machetti F]]
-[[Category: Machetti, F.]]
+[[Category: Mannino C]]
-[[Category: Mannino, C.]]
+[[Category: Nievo M]]
-[[Category: Nievo, M.]]
+[[Category: Papakyriakou A]]
-[[Category: Papakyriakou, A.]]
-[[Category: drug design]]
-[[Category: hydroxamic acid]]
-[[Category: inhibitor]]
-[[Category: macrophage metalloelastase]]
-[[Category: matrix metalloproteinase]]
-[[Category: mmp-12]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:35:26 2008''