3EQ7: Prolyl Oligopeptidase Complexed With R-pro-(decarboxy-pro)-type Inhibitors

Citation:
Abstract
Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.
PDB ID: 3EQ7Download
MMDB ID: 76210
PDB Deposition Date: 2008/9/30
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.89  Å
Source Organism:
Similar Structures:
Biological Unit for 3EQ7: monomeric; determined by author and by software (PISA)
Molecular Components in 3EQ7
Label Count Molecule
Protein (1 molecule)
1
Prolyl Endopeptidase(Gene symbol: PREP)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.