PDBsum entry 1zkc

Isomerase

PDB id: 1zkc

Contents

Protein chain

187 a.a. *

Ligands

BME ×2

Waters ×581

* Residue conservation analysis

PDB id:

1zkc

Name:

Isomerase

Title:

Crystal structure of the cyclophiln_ring domain of human peptidylprolyl isomerase (cyclophilin)-like 2 isoform b

Structure:

Peptidyl-prolyl cis-trans isomerase like 2. Chain: a, b. Fragment: sequence databank residues 20-197. Synonym: ppiase, rotamase, cyclophilin-60, cyclophilin-like protein cyp-60, cyclophilin-ring domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ppil2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.65Å R-factor: 0.158 R-free: 0.194

Authors:

J.R.Walker,T.Davis,E.M.Newman,F.Mackenzie,J.Weigelt,M.Sundstrom, C.Arrowsmith,A.Edwards,A.Bochkarev,S.Dhe-Paganon,Structural Genomics Consortium (Sgc)

Key ref:

T.L.Davis et al. (2010). Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. Plos Biol, 8, e1000439. PubMed id: 20676357

Date:

02-May-05 Release date: 16-Aug-05

Protein chains

Q13356  (PPIL2_HUMAN) -  RING-type E3 ubiquitin-protein ligase PPIL2 from Homo sapiens

Seq: 520 a.a.

Struc: 187 a.a.*

* PDB and UniProt seqs differ at 9 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

Plos Biol 8:e1000439 (2010)

PubMed id: 20676357

Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.

T.L.Davis, J.R.Walker, V.Campagna-Slater, P.J.Finerty, R.Paramanathan, G.Bernstein, F.MacKenzie, W.Tempel, H.Ouyang, W.H.Lee, E.Z.Eisenmesser, S.Dhe-Paganon.

ABSTRACT

Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design drug specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure:function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform specificity for both in vivo substrates and drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in this region support our observations. Our data indicate that unique isoform determinants exist that may be exploited for development of selective ligands and suggest that the currently available small-molecule and peptide-based ligands for this class of enzyme are insufficient for isoform specificity.