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dc.contributor.authorGee, Christine L
dc.contributor.authorDrinkwater, Nyssa
dc.contributor.authorTyndall, Joel DA
dc.contributor.authorGrunewald, Gary L
dc.contributor.authorWu, Qian
dc.contributor.authorMcLeish, Michael J
dc.contributor.authorMartin, Jennifer L
dc.date.accessioned2017-09-26T22:00:20Z
dc.date.available2017-09-26T22:00:20Z
dc.date.issued2007
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/jm0703385
dc.identifier.urihttp://hdl.handle.net/10072/347439
dc.description.abstractShape 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 Å3 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom4845
dc.relation.ispartofpageto4853
dc.relation.ispartofissue20
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume50
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchMedicinal and biomolecular chemistry not elsewhere classified
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode340499
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode3214
dc.titleEnzyme adaptation to inhibitor binding: A cryptic binding site in phenylethanolamine N-methyltransferase
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


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