Biomaterial Database

Structural basis for high-affinity peptide inhibition of human Pin1. 2007

Yan Zhang, and Sebastian Daum, and Dirk Wildemann, and Xiao Zhen Zhou, and Mark A Verdecia, and Marianne E Bowman, and Christian Lücke, and Tony Hunter, and Kun-Ping Lu, and Gunter Fischer, and Joseph P Noel

The Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.

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.

UI	MeSH Term	Description	Entries
D007536	Isomerism	The phenomenon whereby certain chemical compounds have structures that are different although the compounds possess the same elemental composition. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)	Isomerisms
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D009842	Oligopeptides	Peptides composed of between two and twelve amino acids.	Oligopeptide
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072340	NIMA-Interacting Peptidylprolyl Isomerase	A highly-conserved peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated SERINE- or THREONINE-PROLINE (pSer/Thr-Pro) motifs and causes conformational changes in certain proteins associated with the CELL CYCLE. It displays a preference for an acidic residue N-terminal to the isomerized proline bond and regulates MITOSIS, possibly by attenuating the mitosis-promoting activity of NIMA-RELATED KINASE 1.	PIN1 Protein,Peptidyl-Prolyl Cis-Trans Isomerase Pin1,Pin1 Peptidylprolyl Isomerase,Isomerase, NIMA-Interacting Peptidylprolyl,Isomerase, Pin1 Peptidylprolyl,NIMA Interacting Peptidylprolyl Isomerase,Peptidyl Prolyl Cis Trans Isomerase Pin1,Peptidylprolyl Isomerase, NIMA-Interacting,Peptidylprolyl Isomerase, Pin1
D001665	Binding Sites	The parts of a macromolecule that directly participate in its specific combination with another molecule.	Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships