2g71: Difference between revisions

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-[[Image:2g71.gif|left|200px]]<br /><applet load="2g71" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2g71, resolution 2.200&Aring;" />
-'''Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy'''<br />
-==Overview==
+==Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy==
-Shape complementarity is a fundamental principle of inhibitor design. Here, we show that an enzyme for which the crystal structure has been determined, (phenylethanolamine N-methyltransferase, PNMT) conceals a cryptic binding, site. This site is revealed upon binding of inhibitors that are double the, size of the physiological substrate. These large inhibitors are not, predicted to bind in that they protrude through the accessible surface, calculated from a PNMT/7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline, (SK&amp;F 29661) crystal structure, yet they are potent inhibitors of PNMT. We, determined structures of the enzyme complexed with large inhibitors and, found that the volume of the active site increases by 140 A3 upon binding., Changes in active site size and shape are brought about by unfavorable, side chain conformations and rigid body helix motions. The energetic cost, is modest, estimated at 2-3 kcal/mol from mutational analyses. Our, findings further underline the importance of protein flexibility in, structure-based inhibitor design studies.
+<StructureSection load='2g71' size='340' side='right'caption='[[2g71]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2g71]] is a 2 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=2G71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G71 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FTS:(3R)-3-(FLUOROMETHYL)-N-(3,3,3-TRIFLUOROPROPYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>FTS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2g71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g71 OCA], [https://pdbe.org/2g71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g71 RCSB], [https://www.ebi.ac.uk/pdbsum/2g71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g71 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN] Converts noradrenaline to adrenaline.
+== 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/g7/2g71_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2g71 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Shape complementarity is a fundamental principle of inhibitor design. Here we show that an enzyme for which the crystal structure has been determined (phenylethanolamine N-methyltransferase, PNMT) conceals a cryptic binding site. This site is revealed upon binding of inhibitors that are double the size of the physiological substrate. These large inhibitors are not predicted to bind in that they protrude through the accessible surface calculated from a PNMT/7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (SK&amp;F 29661) crystal structure, yet they are potent inhibitors of PNMT. We determined structures of the enzyme complexed with large inhibitors and found that the volume of the active site increases by 140 A3 upon binding. Changes in active site size and shape are brought about by unfavorable side chain conformations and rigid body helix motions. The energetic cost is modest, estimated at 2-3 kcal/mol from mutational analyses. Our findings further underline the importance of protein flexibility in structure-based inhibitor design studies.
-==About this Structure==
+Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase.,Gee CL, Drinkwater N, Tyndall JD, Grunewald GL, Wu Q, McLeish MJ, Martin JL J Med Chem. 2007 Oct 4;50(20):4845-53. Epub 2007 Sep 11. PMID:17845018<ref>PMID:17845018</ref>
-G71 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SAH:'>SAH</scene>, <scene name='pdbligand=FTS:'>FTS</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.28 2.1.1.28] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G71 OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase., Gee CL, Drinkwater N, Tyndall JD, Grunewald GL, Wu Q, McLeish MJ, Martin JL, J Med Chem. 2007 Oct 4;50(20):4845-4853. Epub 2007 Sep 11. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17845018 17845018]
+</div>
+<div class="pdbe-citations 2g71" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phenylethanolamine N-methyltransferase|Phenylethanolamine N-methyltransferase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Phenylethanolamine N-methyltransferase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Gee CL]]
-[[Category: Gee, C.L.]]
+[[Category: Martin JL]]
-[[Category: Martin, J.L.]]
+[[Category: Tyndall JDA]]
-[[Category: Tyndall, J.D.A.]]
-[[Category: FTS]]
-[[Category: GOL]]
-[[Category: SAH]]
-[[Category: methyltransferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:55:39 2008''