 |
PDBsum entry 2hq6
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Structural and biochemical characterization of the human cyclophilin family of peptidyl-Prolyl isomerases.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
Plos Biol, 2010,
8,
e1000439.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Creation of genome-Wide protein expression libraries using random activation of gene expression.
|
|
|
Authors
|
|
J.J.Harrington,
B.Sherf,
S.Rundlett,
P.D.Jackson,
R.Perry,
S.Cain,
C.Leventhal,
M.Thornton,
R.Ramachandran,
J.Whittington,
L.Lerner,
D.Costanzo,
K.Mcelligott,
S.Boozer,
R.Mays,
E.Smith,
N.Veloso,
A.Klika,
J.Hess,
K.Cothren,
K.Lo,
J.Offenbacher,
J.Danzig,
M.Ducar.
|
|
|
Ref.
|
|
Nat Biotechnol, 2001,
19,
440-445.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
Figure 1. Schematic diagram of gene expression using a RAGE
vector. A RAGE vector is shown integrating into a host cell
chromosome upstream of an endogenous gene. Following
integration, the vector becomes operably linked to the
downstream gene, thereby allowing transcription to occur from
the vector-encoded promoter through the endogenous gene. RNA
splicing removes intervening sequences between the
vector-encoded exon, also called the activation exon, and the
first downstream splice acceptor site. Endogenous introns are
removed and the message is polyadenylated. In the example shown
here, the vector integrated upstream of exon II (i.e., upstream
of the 5'-most splice acceptor site); however, the vector may
also integrate into downstream introns or exons to produce
various truncated forms of the activated gene. S/D, splice donor
site.
|
|
Figure 3.
Figure 3. Comparison of experimental and predicted transcript
structure. The structures of naturally expressed transcripts,
RAGE-activated transcripts, and predicted transcripts from known
genes were compared. Analysis of these transcripts highlights
the fidelity of RAGE transcripts and illustrates errors that
handicap gene prediction and the disagreement between the
predictions of different gene-finding algorithms. Protein-coding
sequence is shown as red bars. Correctly spliced exons are shown
as open boxes. Missed exons are shown as gaps. Mis-spliced exons
are shown as gray boxes. The sites of insertion of overpredicted
exons are indicated by red triangles (internal exons) or red
boxes (terminal exons). The RAGE vector exons are shown as black
boxes. (A) Analysis of transcripts from the NME7 gene (GenBank
accession no. 7242158). (B) Analysis of transcripts from the RNA
binding motif protein 9 gene (GenBank accession no. 7657503).
(C) Analysis of transcripts from the Ku auto-antigen gene
(GenBank accession no. 250496).
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Characterization of human colon cancer antigens recognized by autologous antibodies.
|
|
|
Authors
|
|
M.J.Scanlan,
Y.T.Chen,
B.Williamson,
A.O.Gure,
E.Stockert,
J.D.Gordan,
O.Türeci,
U.Sahin,
M.Pfreundschuh,
L.J.Old.
|
|
|
Ref.
|
|
Int J Cancer, 1998,
76,
652-658.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
