2Q5A

human Pin1 bound to L-PEPTIDE

Replaces:  2ITI

Summary for 2Q5A

• Entry DOI: 10.2210/pdb2q5a/pdb
• Related: 1pin 2itk
• Descriptor: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, Five residue peptide, 3,6,9,12,15,18-HEXAOXAICOSANE, ... (4 entities in total)
• Functional Keywords: isomerase ww domain, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q13526
• Total number of polymer chains: 2
• Total formula weight: 19625.73

Authors

Noel, J.P.,Zhang, Y. (deposition date: 2007-05-31, release date: 2007-06-26, Last modification date: 2011-07-13)

Primary citation

Zhang, Y.,Daum, S.,Wildemann, D.,Zhou, X.Z.,Verdecia, M.A.,Bowman, M.E.,Lucke, C.,Hunter, T.,Lu, K.P.,Fischer, G.,Noel, J.P.
Structural basis for high-affinity peptide inhibition of human Pin1.
Acs Chem.Biol., 2:320-328, 2007

PubMed 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.

PubMed: 17518432
DOI: 10.1021/cb7000044

Experimental method

X-RAY DIFFRACTION (1.5 Å)