title: Structural basis for high-affinity peptide inhibition of human Pin1.
abstract: Human Pin1 is a key regulator of cell-cycle progression and plays growth-promoting roles in human cancers. High-affinity inhibitors of Pin1 may provide a unique opportunity for disrupting oncogenic pathways. Here we report two high-resolution X-ray crystal structures of human Pin1 bound to non-natural peptide inhibitors. The structures of the bound high-affinity peptides identify a type-I beta-turn conformation for Pin1 prolyl peptide isomerase domain-peptide binding and an extensive molecular interface for high-affinity recognition. Moreover, these structures suggest chemical elements that may further improve the affinity and pharmacological properties of future peptide-based Pin inhibitors. Finally, an intramolecular hydrogen bond observed in both peptide complexes mimics the cyclic conformation of FK506 and rapamycin. Both FK506 and rapamycin are clinically important inhibitors of other peptidyl-prolyl cis-trans isomerases. This comparative discovery suggests that a cyclic peptide polyketide bridge, like that found in FK506 and rapamycin or a similar linkage, may significantly improve the binding affinity of structure-based Pin1 inhibitors.
authors.affiliation: The Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sebastian
authors.initials: S
authors.lastname: Daum
authors.forename: Dirk
authors.initials: D
authors.lastname: Wildemann
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Mark A
authors.initials: MA
authors.lastname: Verdecia
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Bowman
authors.forename: Christian
authors.initials: C
authors.lastname: Lücke
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.forename: Kun-Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Noel
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009842:Oligopeptides; D019151:Peptide Library; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase