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

Journal Article


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 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. © 2007 American Chemical Society.

UOW Authors


  •   Gee, Christine (external author)
  •   Drinkwater, Nyssa (external author)
  •   Tyndall, Joel (external author)
  •   Grunewald, Gary (external author)
  •   Wu, Qian (external author)
  •   Mcleish, Michael (external author)
  •   Martin, Jennifer

Publication Date


  • 2007

Citation


  • Gee, C. L., Drinkwater, N., Tyndall, J. D. A., Grunewald, G. L., Wu, Q., Mcleish, M. J. & Martin, J. L. (2007). Enzyme adaptation to inhibitor binding: A cryptic binding site in phenylethanolamine N-methyltransferase. Journal of Medicinal Chemistry, 50 (20), 4845-4853.

Scopus Eid


  • 2-s2.0-34948851830

Number Of Pages


  • 8

Start Page


  • 4845

End Page


  • 4853

Volume


  • 50

Issue


  • 20

Place Of Publication


  • United States

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 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. © 2007 American Chemical Society.

UOW Authors


  •   Gee, Christine (external author)
  •   Drinkwater, Nyssa (external author)
  •   Tyndall, Joel (external author)
  •   Grunewald, Gary (external author)
  •   Wu, Qian (external author)
  •   Mcleish, Michael (external author)
  •   Martin, Jennifer

Publication Date


  • 2007

Citation


  • Gee, C. L., Drinkwater, N., Tyndall, J. D. A., Grunewald, G. L., Wu, Q., Mcleish, M. J. & Martin, J. L. (2007). Enzyme adaptation to inhibitor binding: A cryptic binding site in phenylethanolamine N-methyltransferase. Journal of Medicinal Chemistry, 50 (20), 4845-4853.

Scopus Eid


  • 2-s2.0-34948851830

Number Of Pages


  • 8

Start Page


  • 4845

End Page


  • 4853

Volume


  • 50

Issue


  • 20

Place Of Publication


  • United States