2obf

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{{STRUCTURE_2obf| PDB=2obf | SCENE= }}
{{STRUCTURE_2obf| PDB=2obf | SCENE= }}
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'''Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)'''
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===Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_17845018}}
==About this Structure==
==About this Structure==
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[[Category: Martin, J L.]]
[[Category: Martin, J L.]]
[[Category: Methyltransferase]]
[[Category: Methyltransferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:33:21 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 06:59:55 2008''

Revision as of 04:00, 29 July 2008

Image:2obf.png

Template:STRUCTURE 2obf

Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)

Template:ABSTRACT PUBMED 17845018

About this Structure

2OBF is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

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:17845018

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