2G71

Structure of hPNMT with inhibitor 3-fluoromethyl-7-trifluoropropyl-THIQ and AdoHcy

Summary for 2G71

• Entry DOI: 10.2210/pdb2g71/pdb
• Related: 1HNN 1N7I 1N7J 1YZ3 2g70 2g72
• Descriptor: Phenylethanolamine N-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, (3R)-3-(FLUOROMETHYL)-N-(3,3,3-TRIFLUOROPROPYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE, ... (5 entities in total)
• Functional Keywords: methyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65233.52

Authors

Tyndall, J.D.A.,Gee, C.L.,Martin, J.L. (deposition date: 2006-02-27, release date: 2007-02-13, Last modification date: 2024-10-30)

Primary citation

Gee, C.L.,Drinkwater, N.,Tyndall, J.D.A.,Grunewald, G.L.,Wu, Q.,McLeish, M.J.,Martin, J.L.
Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase
J.Med.Chem., 50:4845-4853, 2007

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.

PubMed: 17845018
DOI: 10.1021/jm0703385

Experimental method

X-RAY DIFFRACTION (2.2 Å)