2g70 | pdb_00002g70
Structure of human PNMT in complex with inhibitor 3-hydroxymethyl-7-nitro-THIQ and AdoMet (SAM)
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Overview
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.
Disease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this Structure
2G70 is a Single protein structure of sequence from Homo sapiens with PO4, SAM and HNT as ligands. Active as Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 Full crystallographic information is available from OCA.
Reference
Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase., Gee CL, Drinkwater N, Tyndall JD, Grunewald GL, Wu Q, McLeish MJ, Martin JL, J Med Chem. 2007 Oct 4;50(20):4845-4853. Epub 2007 Sep 11. PMID:17845018
Page seeded by OCA on Mon Nov 12 22:15:39 2007
