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3ntp

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3ntp, resolution 1.76Å ()
Sites: and
Ligands: ,
Gene: PIN1 (Homo sapiens)
Activity: Peptidylprolyl isomerase, with EC number 5.2.1.8
Related: 2itk, 2q5a


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Human Pin1 complexed with reduced amide inhibitor

Publication Abstract from PubMed

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.

A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state., Xu GG, Zhang Y, Mercedes-Camacho AY, Etzkorn FA, Biochemistry. 2011 Nov 8;50(44):9545-50. Epub 2011 Oct 18. PMID:21980916

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

3ntp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Xu GG, Zhang Y, Mercedes-Camacho AY, Etzkorn FA. A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state. Biochemistry. 2011 Nov 8;50(44):9545-50. Epub 2011 Oct 18. PMID:21980916 doi:10.1021/bi201055c

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