2g8n: Difference between revisions
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'''Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy''' | {{Structure | ||
|PDB= 2g8n |SIZE=350|CAPTION= <scene name='initialview01'>2g8n</scene>, resolution 2.150Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=F83:(3R)-N-(4-CHLOROPHENYL)-3-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>F83</scene> and <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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= | |||
}} | |||
'''Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2G8N is a [ | 2G8N 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=2G8N OCA]. | ||
==Reference== | ==Reference== | ||
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase., Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR, J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:[http:// | Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase., Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR, J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16942016 16942016] | ||
[[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 17:01:44 2008'' | ||
Revision as of 15:01, 20 March 2008
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| 2g8n, resolution 2.150Å | |||||||||||||
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| Ligands: | F83 and SAH | ||||||||||||
| Activity: | Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy
Overview
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.
Disease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this Structure
2G8N is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase., Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR, J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:16942016
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