2g71: Difference between revisions
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[[Image:2g71.gif|left|200px]] | [[Image:2g71.gif|left|200px]] | ||
'''Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy''' | {{Structure | ||
|PDB= 2g71 |SIZE=350|CAPTION= <scene name='initialview01'>2g71</scene>, resolution 2.200Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=FTS:(3R)-3-(FLUOROMETHYL)-N-(3,3,3-TRIFLUOROPROPYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>FTS</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene> | |||
|ACTIVITY= [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] | |||
|GENE= pnmt ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2G71 is a [ | 2G71 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=2G71 OCA]. | ||
==Reference== | ==Reference== | ||
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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/17845018 17845018] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phenylethanolamine N-methyltransferase]] | [[Category: Phenylethanolamine N-methyltransferase]] | ||
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[[Category: methyltransferase]] | [[Category: methyltransferase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:01:10 2008'' | ||
Revision as of 18:01, 20 March 2008
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| , resolution 2.200Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Gene: | pnmt (Homo sapiens) | ||||||
| Activity: | Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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.
DiseaseDisease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this StructureAbout this Structure
2G71 is a Single protein structure of sequence from Homo sapiens. 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):4845-53. Epub 2007 Sep 11. PMID:17845018
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