3i6c
From Proteopedia
Structure-Based Design of Novel PIN1 Inhibitors (II)
Structural highlights
Function[PIN1_HUMAN] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.[1] [2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFollowing the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. Structure-based design of novel human Pin1 inhibitors (II).,Dong L, Marakovits J, Hou X, Guo C, Greasley S, Dagostino E, Ferre R, Johnson MC, Kraynov E, Thomson J, Pathak V, Murray BW Bioorg Med Chem Lett. 2010 Apr 1;20(7):2210-4. Epub 2010 Feb 14. PMID:20207139[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Peptidylprolyl isomerase | Ferre, R A | Greasley, S E | Cell cycle | Isomerase | Nucleus | Phosphoprotein | Ppiase | Rotamase | Sbdd | Small molecule
