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PDBsum entry 1m9f

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protein Protein-protein interface(s) links
Isomerase/viral protein PDB id
1m9f
Jmol
Contents
Protein chains
165 a.a. *
146 a.a. *
135 a.a. *
Waters ×576
* Residue conservation analysis
PDB id:
1m9f
Name: Isomerase/viral protein
Title: X-ray crystal structure of cyclophilin a/HIV-1 ca n- terminal domain (1-146) m-type h87a,a88m complex.
Structure: Cyclophilin a. Chain: a, b. Synonym: peptidyl-prolyl cis-trans isomerase a, ppiase, rotamase, cyclosporin a-binding protein. Engineered: yes. HIV-1 capsid. Chain: c, d. Fragment: n-terminal domain. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: ca.
Biol. unit: Dimer (from PQS)
Resolution:
1.73Å     R-factor:   0.172     R-free:   0.220
Authors: B.R.Howard,F.F.Vajdos,S.Li,W.I.Sundquist,C.P.Hill
Key ref:
B.R.Howard et al. (2003). Structural insights into the catalytic mechanism of cyclophilin A. Nat Struct Biol, 10, 475-481. PubMed id: 12730686 DOI: 10.1038/nsb927
Date:
28-Jul-02     Release date:   27-May-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P62937  (PPIA_HUMAN) -  Peptidyl-prolyl cis-trans isomerase A
Seq:
Struc:
165 a.a.
165 a.a.
Protein chain
Pfam   ArchSchema ?
Q72497  (Q72497_9HIV1) -  Gag polyprotein
Seq:
Struc:
500 a.a.
146 a.a.*
Protein chain
Pfam   ArchSchema ?
Q72497  (Q72497_9HIV1) -  Gag polyprotein
Seq:
Struc:
500 a.a.
135 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.5.2.1.8  - Peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)
Peptidylproline (omega=180)
= peptidylproline (omega=0)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   8 terms 
  Biological process     viral reproduction   18 terms 
  Biochemical function     protein binding     7 terms  

 

 
    Added reference    
 
 
DOI no: 10.1038/nsb927 Nat Struct Biol 10:475-481 (2003)
PubMed id: 12730686  
 
 
Structural insights into the catalytic mechanism of cyclophilin A.
B.R.Howard, F.F.Vajdos, S.Li, W.I.Sundquist, C.P.Hill.
 
  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.
 
  Selected figure(s)  
 
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.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22407016 M.E.Caines, K.Bichel, A.J.Price, W.A.McEwan, G.J.Towers, B.J.Willett, S.M.Freund, and L.C.James (2012).
Diverse HIV viruses are targeted by a conformationally dynamic antiviral.
  Nat Struct Mol Biol, 19, 411-416.
PDB codes: 4dga 4dgb 4dgc 4dgd 4dge
20602248 A.Galat, and J.Bua (2010).
Molecular aspects of cyclophilins mediating therapeutic actions of their ligands.
  Cell Mol Life Sci, 67, 3467-3488.  
20140189 F.P.Davis, and A.Sali (2010).
The overlap of small molecule and protein binding sites within families of protein structures.
  PLoS Comput Biol, 6, e1000668.  
20364129 M.Lammers, H.Neumann, J.W.Chin, and L.C.James (2010).
Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization.
  Nat Chem Biol, 6, 331-337.
PDB codes: 2x25 2x2a 2x2c 2x2d
  20955553 N.Inagaki, H.Takeuchi, M.Yokoyama, H.Sato, A.Ryo, H.Yamamoto, M.Kawada, and T.Matano (2010).
A structural constraint for functional interaction between N-terminal and C-terminal domains in simian immunodeficiency virus capsid proteins.
  Retrovirology, 7, 90.  
20676357 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, and S.Dhe-Paganon (2010).
Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.
  PLoS Biol, 8, e1000439.  
19767750 A.J.Price, F.Marzetta, M.Lammers, L.M.Ylinen, T.Schaller, S.J.Wilson, G.J.Towers, and L.C.James (2009).
Active site remodeling switches HIV specificity of antiretroviral TRIMCyp.
  Nat Struct Mol Biol, 16, 1036-1042.
PDB codes: 2wlv 2wlw
19825046 A.P.Mascarenhas, and K.Musier-Forsyth (2009).
The capsid protein of human immunodeficiency virus: interactions of HIV-1 capsid with host protein factors.
  FEBS J, 276, 6118-6127.  
19128175 D.Hamelberg, and J.A.McCammon (2009).
Mechanistic insight into the role of transition-state stabilization in cyclophilin A.
  J Am Chem Soc, 131, 147-152.  
19956261 J.S.Fraser, M.W.Clarkson, S.C.Degnan, R.Erion, D.Kern, and T.Alber (2009).
Hidden alternative structures of proline isomerase essential for catalysis.
  Nature, 462, 669-673.
PDB codes: 3k0m 3k0n 3k0o 3k0p 3k0q
  19319933 J.Schlegel, G.S.Armstrong, J.S.Redzic, F.Zhang, and E.Z.Eisenmesser (2009).
Characterizing and controlling the inherent dynamics of cyclophilin-A.
  Protein Sci, 18, 811-824.  
19118358 J.Xu, D.Baldwin, C.Kindrachuk, and D.D.Hegedus (2009).
Comparative EST analysis of a Zoophthora radicans isolate derived from Pieris brassicae and an isogenic strain adapted to Plutella xylostella.
  Microbiology, 155, 174-185.  
19185003 S.B.Moparthi, P.Hammarström, and U.Carlsson (2009).
A nonessential role for Arg 55 in cyclophilin18 for catalysis of proline isomerization during protein folding.
  Protein Sci, 18, 475-479.  
19282959 V.Leone, G.Lattanzi, C.Molteni, and P.Carloni (2009).
Mechanism of action of cyclophilin a explored by metadynamics simulations.
  PLoS Comput Biol, 5, e1000309.  
18819019 X.Song, L.Wang, L.Song, J.Zhao, H.Zhang, P.Zheng, L.Qiu, X.Liu, and L.Wu (2009).
A cyclophilin A inducible expressed in gonad of zhikong scallop Chlamys farreri.
  Mol Biol Rep, 36, 1637-1645.  
19656870 Y.Li, A.K.Kar, and J.Sodroski (2009).
Target cell type-dependent modulation of human immunodeficiency virus type 1 capsid disassembly by cyclophilin A.
  J Virol, 83, 10951-10962.  
18406133 B.K.Ganser-Pornillos, M.Yeager, and W.I.Sundquist (2008).
The structural biology of HIV assembly.
  Curr Opin Struct Biol, 18, 203-217.  
18193057 M.O.Lasaro, N.Tatsis, S.E.Hensley, J.C.Whitbeck, S.W.Lin, J.J.Rux, E.J.Wherry, G.H.Cohen, R.J.Eisenberg, and H.C.Ertl (2008).
Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses.
  Nat Med, 14, 205-212.  
18397323 T.L.Davis, J.R.Walker, H.Ouyang, F.MacKenzie, C.Butler-Cole, E.M.Newman, E.Z.Eisenmesser, and S.Dhe-Paganon (2008).
The crystal structure of human WD40 repeat-containing peptidylprolyl isomerase (PPWD1).
  FEBS J, 275, 2283-2295.
PDB code: 2a2n
18342330 V.Thai, P.Renesto, C.A.Fowler, D.J.Brown, T.Davis, W.Gu, D.D.Pollock, D.Kern, D.Raoult, and E.Z.Eisenmesser (2008).
Structural, biochemical, and in vivo characterization of the first virally encoded cyclophilin from the Mimivirus.
  J Mol Biol, 378, 71-86.
PDB code: 2ose
18757560 Z.Zhang, L.Lu, W.G.Noid, V.Krishna, J.Pfaendtner, and G.A.Voth (2008).
A systematic methodology for defining coarse-grained sites in large biomolecules.
  Biophys J, 95, 5073-5083.  
17715216 C.Song, and C.Aiken (2007).
Analysis of human cell heterokaryons demonstrates that target cell restriction of cyclosporine-resistant human immunodeficiency virus type 1 mutants is genetically dominant.
  J Virol, 81, 11946-11956.  
17475650 H.Song, E.E.Nakayama, M.Yokoyama, H.Sato, J.A.Levy, and T.Shioda (2007).
A single amino acid of the human immunodeficiency virus type 2 capsid affects its replication in the presence of cynomolgus monkey and human TRIM5alphas.
  J Virol, 81, 7280-7285.  
17876319 K.P.Lu, G.Finn, T.H.Lee, and L.K.Nicholson (2007).
Prolyl cis-trans isomerization as a molecular timer.
  Nat Chem Biol, 3, 619-629.  
17299408 M.A.Rits, K.A.van Dort, C.Münk, A.B.Meijer, and N.A.Kootstra (2007).
Efficient transduction of simian cells by HIV-1-based lentiviral vectors that contain mutations in the capsid protein.
  Mol Ther, 15, 930-937.  
17912258 T.R.Hupp, and M.Walkinshaw (2007).
Multienzyme assembly of a p53 transcription complex.
  Nat Struct Mol Biol, 14, 885-887.  
17075133 D.Trzesniak, and W.F.van Gunsteren (2006).
Catalytic mechanism of cyclophilin as observed in molecular dynamics simulations: pathway prediction and reconciliation of X-ray crystallographic and NMR solution data.
  Protein Sci, 15, 2544-2551.  
17005650 M.Takano-Maruyama, Y.Ohara, K.Asakura, and T.Okuwa (2006).
Theiler's murine encephalomyelitis virus leader protein amino acid residue 57 regulates subgroup-specific virus growth on BHK-21 cells.
  J Virol, 80, 12025-12031.  
16372262 P.Ghezzi, S.Casagrande, T.Massignan, M.Basso, E.Bellacchio, L.Mollica, E.Biasini, R.Tonelli, I.Eberini, E.Gianazza, W.W.Dai, M.Fratelli, M.Salmona, B.Sherry, and V.Bonetto (2006).
Redox regulation of cyclophilin A by glutathionylation.
  Proteomics, 6, 817-825.  
16409630 P.K.Agarwal (2006).
Enzymes: An integrated view of structure, dynamics and function.
  Microb Cell Fact, 5, 2.  
15990872 F.Edlich, M.Weiwad, F.Erdmann, J.Fanghänel, F.Jarczowski, J.U.Rahfeld, and G.Fischer (2005).
Bcl-2 regulator FKBP38 is activated by Ca2+/calmodulin.
  EMBO J, 24, 2688-2699.  
15845542 K.Piotukh, W.Gu, M.Kofler, D.Labudde, V.Helms, and C.Freund (2005).
Cyclophilin A binds to linear peptide motifs containing a consensus that is present in many human proteins.
  J Biol Chem, 280, 23668-23674.  
15735342 L.L.Huang, X.M.Zhao, C.Q.Huang, L.Yu, and Z.X.Xia (2005).
Structure of recombinant human cyclophilin J, a novel member of the cyclophilin family.
  Acta Crystallogr D Biol Crystallogr, 61, 316-321.
PDB code: 1xyh
15626706 M.Bon Homme, C.Carter, and S.Scarlata (2005).
The cysteine residues of HIV-1 capsid regulate oligomerization and cyclophilin A-induced changes.
  Biophys J, 88, 2078-2088.  
15706440 Q.Yao, M.Li, H.Yang, H.Chai, W.Fisher, and C.Chen (2005).
Roles of cyclophilins in cancers and other organ systems.
  World J Surg, 29, 276-280.  
15229879 P.K.Agarwal (2004).
Cis/trans isomerization in HIV-1 capsid protein catalyzed by cyclophilin A: insights from computational and theoretical studies.
  Proteins, 56, 449-463.  
14610182 S.Tang, T.Murakami, N.Cheng, A.C.Steven, E.O.Freed, and J.G.Levin (2003).
Human immunodeficiency virus type 1 N-terminal capsid mutants containing cores with abnormally high levels of capsid protein and virtually no reverse transcriptase.
  J Virol, 77, 12592-12602.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.