+ Translate
+ Most Popular
Gaucher's disease;thirty-two years experience at Siriraj Hospital
A study of Macrobathra Meyrick from China (Lepidoptera, Cosmopterigidae)
First occurrence in ores of tetragonal chalcocite
Effects of trace element nutrition on sleep patterns in adult women
N.Z. range management guidelines. 2. Design of grazing management systems for tussock country
A case of lipoma of the esophagus
A revision of world Acanthosomatidae (Heteroptera: Pentatomidae): keys to and descriptions of subfamilies, tribes and genera, with designation of types
Life history of the coronate scyphozoan Linuche unguiculata (Swartz, 1788)
Perceptual restoration of obliterated sounds
Mutagenicity studies on two chromium(III) coordination compounds
The formation of the skeleton. I. Growth of a long bone. 1st appearance of a center of calcification
Leucopenia and abnormal liver function in travellers on malaria chemoprophylaxis
The joint commission: four key root causes loom large in sentinel event data
Treatment of vitiligo with topical 15% lactic acid solution in combination with ultra violet-A
Behaviour of dairy cows within three hours after feed supply: I. Influence of housing type and time elapsing after feed supply
Observations of the propagation velocity and formation mechanism of burst fractures caused by gunshot
Management and control of patients with type 2 diabetes mellitus in Lebanon: results from the International Diabetes Management Practices Study (IDMPS)
The diet composition and nutritional knowledge of patients with anorexia nervosa
Physoporella croatica Herak, 1958 of the Slovak karst Anisian (Slovakia, the West Carpathians Mts.)
Bright lights, big noise. How effective are vehicle warning systems?
Ein Plesiosaurier-Rest mit Magensteinen aus mittlerem Lias von Quedlinburg
Incidence of Chlamydia trachomatis in patients with sterility
Monster soup: the microscope and Victorian fantasy
Preliminary tests with residual sprays against poultry lice
Duration of the life of plants in phylogeny

The molecular replacement solution and X-ray refinement to 2.8 A of a decameric complex of human cyclophilin A with the immunosuppressive drug cyclosporin A

The molecular replacement solution and X-ray refinement to 2.8 A of a decameric complex of human cyclophilin A with the immunosuppressive drug cyclosporin A

Journal of Molecular Biology 244(4): 385-409

ISSN/ISBN: 0022-2836

PMID: 7990129

DOI: 10.1006/jmbi.1994.1738

The X-ray structure of a decameric form of a complex of human cyclophilin A (CypA) with the immunosuppressive drug cyclosporin A (CsA) has been determined. The crystals of space group P4-32-12 with cell dimensions a = b = 95.2 ANG , c = 280.0 ANG have five copies of the cyclophilin A/cyclosporin A complex in the asymmetric unit. The structure was solved by molecular replacement techniques, using a known cyclophilin A model. Procedures were developed to construct a self-rotation function using the results of cross-rotation searches. The comparison of experimental and constructed self-rotation maps was an important aid in selecting the correct rotation function solution. The translation functions revealed the presence of a cyclic pentamer. A crystallographic dimer axis passes through the non-crystallographic 5-fold rotation axis of the pentameric asymmetric unit, and generates a decameric "sandwich" of CypA/CsA heterodimers that has 52 symmetry. The five CypA/CsA protomers were refined independently using all data to 2.8 ANG giving a final crystallographic R-factor of 15.7%. Despite the constraints due to the packing arrangement within the decamer, the CypA and CsA conformations are similar to other CypA/CsA structures determined by X-ray crystallography and NMR spectroscopy. The hydrophobic CsA molecules are embedded in the middle of the decameric sandwich with only 20% of their surface exposed to solvent. The binding loop of CsA (residues 1 to 3 and 9 to 11) comprising 42% of the CsA surface, is buried in the peptidyl-prolyl-cis-trans isomerase active site of the cognate binding partner CypA, while the effector loops (residues 4 to 8) packs in the core of the decamer making hydrogen-bonding and van der Waals contacts with three neighbouring molecules. The environment of CsA in the decamer has been analysed and may provide a mimic for the interactions likely to occur between the CypA/CsA complex and its biological target calcineurin. There is no evidence to suggest that the decameric sandwich itself plays a role in immunosuppression by inhibiting calcineurin. However, the chaperone/foldase activity of CypA could require oligomer formation for its biological function.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 009599949

Download citation: RISBibTeXText

Related references

X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature 361(6407): 91-94, 1993

Protein-protein and protein-drug interactions in a decameric cyclophilin cyclosporin complex. Experientia 49(ABSTR ): A35, 1993

Crystal structure of murine cyclophilin C complexed with immunosuppressive drug cyclosporin A. Proceedings of the National Academy of Sciences of the United States of America 90(24): 11850-11854, 1993

Solution structure of the cyclosporin A/cyclophilin complex by NMR. Nature 361(6407): 88-91, 1993

Three-dimensional solution structure of the cyclosporin A-cyclophilin complex by NMR. Journal of Cellular Biochemistry Suppl 1993(17 Part C): 285, 1993

Determination of the NMR solution structure of the cyclophilin A-cyclosporin A complex. Journal of Biomolecular Nmr 4(4): 463-482, 1994

Molecular modeling studies in the complex between cyclophilin and cyclosporin A. Protein Engineering 5(5): 391-397, 1992

A proposed molecular model for the interaction of calcineurin with the cyclosporin A-cyclophilin A complex. Bioorganic and Medicinal Chemistry 7(7): 1389-1402, 1999

X-ray structure of a cyclophilin B/cyclosporin complex: comparison with cyclophilin A and delineation of its calcineurin-binding domain. Proceedings of the National Academy of Sciences of the United States of America 91(11): 5183-5186, 1994

Cyclophilin residues that affect noncompetitive inhibition of the protein serine phosphatase activity of calcineurin by the cyclophilin.cyclosporin A complex. Biochemistry 33(9): 2380-2388, 1994

Crystal structure of human cyclophilin D in complex with its inhibitor, cyclosporin A at 0.96-A resolution. Proteins 70(4): 1635-1639, 2008

Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A?. Journal of Experimental Medicine 173(3): 619-628, 1991

Comparison of the properties of the CsA analogs monoacetyl CyC (o-acetyl-threonine2 cyclosporin) and methyl-alanyl CsA (N-methyl-L-alanyl6 cyclosporin); monoacetyl cyclosporin is immunosuppressive without binding to cyclophilin. Clinical and Experimental Immunology 89(1): 136-142, 1992

The mutant Escherichia coli F112W cyclophilin binds cyclosporin A in nearly identical conformation as human cyclophilin. Biochemistry 33(19): 5711-5720, 1994

Determination of cyclosporin a and its immunosuppressive metabolites with a competitive cyclophilin binding assay. Journal of Clinical Chemistry and Clinical Biochemistry 26(11): 772, 1988