 |
PDBsum entry 1m9e
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Isomerase/viral protein
|
PDB id
|
|
|
|
1m9e
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
164 a.a.
|
|
|
|
|
|
|
|
|
|
|
146 a.a.
|
|
|
|
|
|
|
|
|
|
|
135 a.a.
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural insights into the catalytic mechanism of cyclophilin a.
|
|
|
Authors
|
|
B.R.Howard,
F.F.Vajdos,
S.Li,
W.I.Sundquist,
C.P.Hill.
|
|
|
Ref.
|
|
Nat Struct Biol, 2003,
10,
475-481.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Cyclophilins constitute a ubiquitous protein family whose functions include
protein folding, transport and signaling. They possess both sequence-specific
binding and proline cis-trans isomerase activities, as exemplified by the
interaction between cyclophilin A (CypA) and the HIV-1 CA protein. Here, we
report crystal structures of CypA in complex with HIV-1 CA protein variants that
bind preferentially with the substrate proline residue in either the cis or the
trans conformation. Cis- and trans-Pro substrates are accommodated within the
enzyme active site by rearrangement of their N-terminal residues and with
minimal distortions in the path of the main chain. CypA Arg55 guanidinium group
probably facilitates catalysis by anchoring the substrate proline oxygen and
stabilizing sp3 hybridization of the proline nitrogen in the transition state.
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. Comparison of CA^N loop conformations. CA^N
residues 86 -93 are shown as a stick representation with side
chains truncated to the C  atom
(except for proline) and carbon atoms colored yellow or orange
(trans) and green (cis). For all figures, the minor (20%
occupied) cis conformations of AMA-A and AMA-A' are not shown
unless explicitly stated. CypA is shown in a ribbon
representation with the Arg55 side chain shown explicitly. (a)
Stereo view showing all eight CA^N structures that adopt the
trans conformation. The four structures that contain Gly89 are
colored yellow; the four Ala89 structures are colored orange.
(b) Same as a but for all eight cis CA^N structures. (c)
Comparison of AAG-A (trans, yellow) and AMG-A (cis, green). (d)
Same as c, but top view. CypA molecular surface colored red. A
model for the transition state is shown with the carbon atoms
colored white. Hydrogen bonds between CypA Arg55 and CA^N Pro90
N and O atoms are shown as dashed lines.
|
|
Figure 3.
Figure 3. Proposed reaction pathway. (a) Mixed trans (80%)
and cis (20%) structures of AMA-A. Maps were calculated before
inclusion of the minor cis conformation in the model. 2F[o] -
F[c] (silver) and F[o] - F[c] (blue) maps are contoured at 1.0
and 2.0  r.m.s.
deviation, respectively. Final refined coordinates for the two
partially occupied conformations are shown in orange (trans) and
green (cis). (b) Top view of AMA-A trans (orange, 80% occupied)
and cis (green, 20% occupied) conformations. Series of red and
orange/green spheres show path of CA^N Ala89 O and C atoms
for intermediate conformations. This path would keep the Ala89
side chain clear of CypA protein and maintains a staggered
conformation. White dashed line; contact between the side chain
of CA^N Ala89 and CypA Arg55 that prevents CA^N Pro90 from
binding fully into the active site when in the trans
conformation. Black dashed lines represent the hydrogen bonds
between CypA Arg55 and CA^N Pro90 O that prevents propagation of
conformational changes to C-terminal residues and the hydrogen
bond to CA^N Pro90 N that promotes catalysis.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2003,
10,
475-481)
copyright 2003.
|
|
|
|
|
|
|
