title: Cyclophilin A complexed with a fragment of HIV-1 gag protein: insights into HIV-1 infectious activity.
abstract: BACKGROUND
  Cyclophilin A (CyPA), a receptor of the immunosuppressive drug cyclosporin A, catalyzes the cis-trans isomerization of peptidyl-prolyl bonds and is required for the infectious activity of human immunodeficiency virus type 1 (HIV-1). The crystal structure of CyPA complexed with a fragment of the HIV-1 gag protein should provide insights into the nature of CyPA-gag interactions and may suggest a role for CyPA in HIV-1 infectious activity.
  
  
  RESULTS
  The crystal structure of CyPA complexed with a 25 amino acid peptide of HIV-1 gag capsid protein (25-mer) was determined and refined to an R factor of 0.195 at 1.8 A resolution. The sequence Ala88-Gly89-Pro90-Ile91 of the gag fragment is the major portion to bind to the active site of CyPA. Two residues of the 25-mer (Pro90-Ile91) bind to CyPA in a similar manner to two residues (Pro-Phe) of the CyPA substrate, succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (AAPF). However, the N-terminus of the 25-mer (Ala88-Gly89) exhibits a different hydrogen-bonding pattern and molecular conformation than AAPF. The peptidyl-prolyl bond between Gly89 and Pro90 of the 25-mer has a trans conformation, in contrast to the cis conformation observed in other known CyPA-peptide complexes. The residue preceding proline, Gly89, has an unfavorable backbone conformation usually only adopted by glycine.
  
  
  CONCLUSIONS
  The unfavorable backbone conformation of Gly89 of the gag 25-mer fragment suggests that binding between HIV-1 gag protein and CyPA requires a special sequence, Gly-Pro. Thus, in HIV-1 infectivity, CyPA is likely to function as a chaperone, rather than as a cis-trans isomerase. However, the observation of similarities between the C termini of the 25-mer and the substrate AAPF means that the involvement of the cis-trans isomerase activity of CyPA cannot be completely ruled out.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Schutkowski
authors.forename: G
authors.initials: G
authors.lastname: Fischer
authors.forename: H
authors.initials: H
authors.lastname: Ke
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D016655:HIV Core Protein p24 / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D019696:Peptidylprolyl Isomerase; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012984:Software
chemical_list: D002352:Carrier Proteins; D016655:HIV Core Protein p24; D010446:Peptide Fragments; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase