7TH1

Structure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor B3

Summary for 7TH1

• Entry DOI: 10.2210/pdb7th1/pdb
• Related: 7TGS 7TGT 7TGU 7TGV
• Descriptor: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, (4S,7S,11R,13E,19S)-N-[2-(2-aminoethoxy)ethyl]-7-benzyl-4-[(3-methylphenyl)methyl]-3,6,12,15,21-pentaoxo-1,3,4,5,6,7,8,9,10,12,15,16,17,18,19,20,21,22-octadecahydro-2H-7,11-methano-2,5,11,16,20-benzopentaazacyclotetracosine-19-carboxamide (3 entities in total)
• Functional Keywords: oxidative stress, necrosis, mitochondrial permeability, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18574.21

Authors

Rangwala, A.M.,Thakur, M.K.,Seeliger, M.A.,Peterson, A.A.,Liu, D.R. (deposition date: 2022-01-10, release date: 2022-08-24, Last modification date: 2023-10-18)

Primary citation

Peterson, A.A.,Rangwala, A.M.,Thakur, M.K.,Ward, P.S.,Hung, C.,Outhwaite, I.R.,Chan, A.I.,Usanov, D.L.,Mootha, V.K.,Seeliger, M.A.,Liu, D.R.
Discovery and molecular basis of subtype-selective cyclophilin inhibitors.
Nat.Chem.Biol., 18:1184-1195, 2022

PubMed Abstract: Although cyclophilins are attractive targets for probing biology and therapeutic intervention, no subtype-selective cyclophilin inhibitors have been described. We discovered novel cyclophilin inhibitors from the in vitro selection of a DNA-templated library of 256,000 drug-like macrocycles for cyclophilin D (CypD) affinity. Iterated macrocycle engineering guided by ten X-ray co-crystal structures yielded potent and selective inhibitors (half maximal inhibitory concentration (IC) = 10 nM) that bind the active site of CypD and also make novel interactions with non-conserved residues in the S2 pocket, an adjacent exo-site. The resulting macrocycles inhibit CypD activity with 21- to >10,000-fold selectivity over other cyclophilins and inhibit mitochondrial permeability transition pore opening in isolated mitochondria. We further exploited S2 pocket interactions to develop the first cyclophilin E (CypE)-selective inhibitor, which forms a reversible covalent bond with a CypE S2 pocket lysine, and exhibits 30- to >4,000-fold selectivity over other cyclophilins. These findings reveal a strategy to generate isoform-selective small-molecule cyclophilin modulators, advancing their suitability as targets for biological investigation and therapeutic development.

PubMed: 36163383
DOI: 10.1038/s41589-022-01116-1

Experimental method

X-RAY DIFFRACTION (1.52 Å)