PDBsum entry 4tot

Isomerase/isomerase inhibitor

PDB id: 4tot

Contents

Protein chains

164 a.a.

11 a.a.

Ligands

P6G ×4

SO4 ×2

Waters ×298

PDB id:

4tot

Name:

Isomerase/isomerase inhibitor

Title:

Crystal structure of rat cyclophilin d in complex with a potent nonimmunosuppressive inhibitor

Structure:

Peptidyl-prolyl cis-trans isomerase f, mitochondrial. Chain: a, b, c, d. Fragment: unp residues 43-206. Synonym: ppiase f,cyclophilin d,cypd,cyclophilin f,rotamase f. Engineered: yes. Nonimmunosuppressive inhibitor. Chain: e, f, g, h. Engineered: yes

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: ppif. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.39Å R-factor: 0.198 R-free: 0.230

Authors:

M.S.Knapp,R.A.Elling

Key ref:

J.Fu et al. (2014). Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition. J Med Chem, 57, 8503-8516. PubMed id: 25310383 DOI: 10.1021/jm500862r

Date:

06-Jun-14 Release date: 12-Nov-14

Protein chains

P29117  (PPIF_RAT) -  Peptidyl-prolyl cis-trans isomerase F, mitochondrial from Rattus norvegicus

Seq: 206 a.a.

Struc: 164 a.a.*

Protein chains

No UniProt id for this chain

Struc: 11 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm500862r

J Med Chem 57:8503-8516 (2014)

PubMed id: 25310383

Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.

J.Fu, M.Tjandra, C.Becker, D.Bednarczyk, M.Capparelli, R.Elling, I.Hanna, R.Fujimoto, M.Furegati, S.Karur, T.Kasprzyk, M.Knapp, K.Leung, X.Li, P.Lu, W.Mergo, C.Miault, S.Ng, D.Parker, Y.Peng, S.Roggo, A.Rivkin, R.L.Simmons, M.Wang, B.Wiedmann, A.H.Weiss, L.Xiao, L.Xie, W.Xu, A.Yifru, S.Yang, B.Zhou, Z.K.Sweeney.

ABSTRACT

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.