Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase.

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Gee CL, Drinkwater N, Tyndall JD, Grunewald GL, Wu Q, McLeish MJ, Martin JL

Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase.

J Med Chem. 2007 Oct 4;50(20):4845-53. Epub 2007 Sep 11.

PubMed ID

17845018 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Phenylethanolamine N-methyltransferase	P11086	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-(4-CHLOROPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE	Phenylethanolamine N-methyltransferase	Ki (nM)	210	N/A	N/A	Details