10.1021/jm0703385.s001
Christine L. Gee
Christine L.
Gee
Nyssa Drinkwater
Nyssa
Drinkwater
Joel D. A. Tyndall
Joel
D. A. Tyndall
Gary L. Grunewald
Gary L.
Grunewald
Qian Wu
Qian
Wu
Michael J. McLeish
Michael J.
McLeish
Jennifer L. Martin
Jennifer L.
Martin
Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine
<i>N</i>-Methyltransferase
American Chemical Society
2007
side chain conformations
crystal structure
site size
140 Å3
Enzyme Adaptation
Cryptic Binding Site
site increases
PNMT
inhibitor design
body helix motions
SK
enzyme complexed
binding site
protein flexibility
2007-10-04 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Enzyme_Adaptation_to_Inhibitor_Binding_A_Cryptic_Binding_Site_in_Phenylethanolamine_i_N_i_Methyltransferase/2982172
Shape complementarity is a fundamental principle of inhibitor design. Here we show that an enzyme for
which the crystal structure has been determined (phenylethanolamine <i>N</i>-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 Å<sup>3</sup> 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.