2g71: Difference between revisions
New page: left|200px<br /> <applet load="2g71" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g71, resolution 2.200Å" /> '''Structure of hPNMT... |
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[[Image:2g71.gif|left|200px]]<br /> | [[Image:2g71.gif|left|200px]]<br /><applet load="2g71" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2g71, resolution 2.200Å" /> | caption="2g71, resolution 2.200Å" /> | ||
'''Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy'''<br /> | '''Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy'''<br /> | ||
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==Overview== | ==Overview== | ||
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&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. | 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&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== | ==About this Structure== | ||
2G71 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 SAH, FTS and GOL 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:// | 2G71 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== | ==Reference== | ||
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[[Category: methyltransferase]] | [[Category: methyltransferase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:55:39 2008'' | ||
Revision as of 13:55, 23 January 2008
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Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy
OverviewOverview
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&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 StructureAbout this Structure
2G71 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 Full crystallographic information is available from OCA.
ReferenceReference
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:17845018
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