2G72: Structure Of Hpnmt With Inhibitor 3-Fluoromethyl-7- Thiomorpholinosulfonamide-Thiq And Adomet

Citation:
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.
PDB ID: 2G72Download
MMDB ID: 44441
PDB Deposition Date: 2006/2/27
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 2G72: monomeric; determined by author and by software (PQS)
Molecular Components in 2G72
Label Count Molecule
Protein (1 molecule)
1
Phenylethanolamine N-methyltransferase(Gene symbol: PNMT)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.