5NOR

Structure of cyclophilin A in complex with 3-methylpyridin-2-amine

Summary for 5NOR

• Entry DOI: 10.2210/pdb5nor/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, 3-methylpyridin-2-amine (3 entities in total)
• Functional Keywords: ligand complex, beta barrel, prolyl cis/trans isomerase, cytosolic, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P62937
• Total number of polymer chains: 1
• Total formula weight: 18252.79

Authors

Georgiou, C.,Mcnae, I.W.,Ioannidis, H.,Julien, M.,Walkinshaw, M.D. (deposition date: 2017-04-13, release date: 2017-07-12, Last modification date: 2024-01-17)

Primary citation

Georgiou, C.,McNae, I.,Wear, M.,Ioannidis, H.,Michel, J.,Walkinshaw, M.
Pushing the Limits of Detection of Weak Binding Using Fragment-Based Drug Discovery: Identification of New Cyclophilin Binders.
J. Mol. Biol., 429:2556-2570, 2017

PubMed Abstract: Fragment-based drug discovery is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance experiments and molecular dynamics simulations for the characterization of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family. The present studies have led to the identification of several structurally novel fragments that bind to diverse Cyp isoforms in distinct pockets with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described.

PubMed: 28673552
DOI: 10.1016/j.jmb.2017.06.016

Experimental method

X-RAY DIFFRACTION (1.8 Å)