3NTP

Human Pin1 complexed with reduced amide inhibitor

Summary for 3NTP

• Entry DOI: 10.2210/pdb3ntp/pdb
• Related: 2itk 2q5A
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, (2R)-2-(acetylamino)-3-[(2S)-2-{[2-(1H-indol-3-yl)ethyl]carbamoyl}pyrrolidin-1-yl]propyl dihydrogen phosphate, 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL, ... (4 entities in total)
• Functional Keywords: prolyl isomerase, phosphorylation regulation, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 1
• Total formula weight: 19347.40

Authors

Zhang, Y. (deposition date: 2010-07-05, release date: 2012-01-04, Last modification date: 2024-04-03)

Primary citation

Xu, G.G.,Zhang, Y.,Mercedes-Camacho, A.Y.,Etzkorn, F.A.
A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.
Biochemistry, 50:9545-9550, 2011

PubMed Abstract: 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-Ψ[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 μM, 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 μM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 Å 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.

PubMed: 21980916
DOI: 10.1021/bi201055c

Experimental method

X-RAY DIFFRACTION (1.762 Å)