Enzyme Adaptation to Inhibitor Binding:  A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase

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 s...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-10, Vol.50 (20), p.4845-4853
Main Authors: Gee, Christine L, Drinkwater, Nyssa, Tyndall, Joel D. A, Grunewald, Gary L, Wu, Qian, McLeish, Michael J, Martin, Jennifer L
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Binding Sites
Biological and medical sciences
Crystallization
Crystallography, X-Ray
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Isoquinolines - chemistry
Medical sciences
Miscellaneous
Models, Molecular
Molecular Structure
Mutation
Pharmacology. Drug treatments
Phenylethanolamine N-Methyltransferase - antagonists & inhibitors
Phenylethanolamine N-Methyltransferase - chemistry
Phenylethanolamine N-Methyltransferase - genetics
Protein Binding
Protein Conformation
Thermodynamics
Transferases
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Summary: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 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0703385