2g71: Difference between revisions
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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" | ||
<applet load="2g71" size=" | |||
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'' | ||
