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PDBsum entry 1m9c

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Isomerase/viral protein PDB id
1m9c
Jmol
Contents
Protein chains
165 a.a. *
146 a.a. *
136 a.a. *
Waters ×144
* 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: 10.1038/nsb927]
PubMed id 12730686
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.
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