3NTP: Human Pin1 Complexed With Reduced Amide Inhibitor

The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R-pSer-Psi[CH(2)N]-Pro-2-(indol-3-yl)ethylamine, 1 [R = fluorenylmethoxycarbonyl (Fmoc)] and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC(50) value of 6.3 muM, which is 4.5-fold better for Pin1 than our comparable ground-state analogue, a cis-amide alkene isostere-containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination and resulted in an IC(50) value of 12 muM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 A resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.
PDB ID: 3NTPDownload
MMDB ID: 96203
PDB Deposition Date: 2010/7/5
Updated in MMDB: 2012/01
Experimental Method:
x-ray diffraction
Resolution: 1.76  Å
Source Organism:
Similar Structures:
Biological Unit: monomeric; determined by author, and by software (PISA)
Molecular Components
Label Count Molecule
Protein (1 molecule)
Peptidyl-prolyl Cis-trans Isomerase Nima-interacting 1
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB