Abstract
Cyclosporin A (CsA) and FK506 are two chemically unrelated immunosuppressants (Figure 4.1) that act in a similar way by blocking specific signal transduction pathways at an early stage of T-cell activation. They inhibit the transcription of genes that produce interleukins (IL-2, IL-3, IL-4), granulocyte-macrophage colony stimulating factor, and interferon-γ (Bierer et al., 1990a; Dumont et al., 1990a) by inhibiting specific transcriptional regulators such as nuclear factor of activated T cells (NF-AT) (Emmel et al., 1989). Although CsA and FK506 have similar biological activities, they bind to different cellular receptors, termed immunophilins. CsA binds to cyclophilin (17.8 kD, 165 aa) (Handschumacher et al., 1984), and FK506 binds to FKBP (11.8 kD, 107 aa) (Harding et al., 1989; Siekierka et al., 1989). Both cyclophilin and FKBP are peptidyl-prolyl cis-trans isomerases (PPIase) that are inhibited by CsA (Fischer et al., 1989; Takahashi et al., 1989) or FK506 (Harding et al., 1989; Siekierka et al., 1989), respectively. In an initial attempt to explain the immunosuppressant activity of CsA and FK506, it was hypothesized that PPIase inhibition was the cause of immunosuppression by inhibiting the folding of proteins involved in the early stages of T-cell activation. However, several pieces of evidence now suggest that the inhibition of PPIase activity is insufficient to cause an immunosuppressive effect (Bierer et al., 1990b).
This is a preview of subscription content, log in via an institution.
Preview
Unable to display preview. Download preview PDF.
References
Aebi, J. D., Deyo, D. T., Sun, C. Q., Guillaume, D., Dunlap, B. E. and Rich, D. H. (1990). Synthesis, conformation and immunosuppressive activities of three analogues of cyclosporin A modified in the 1-position. J. Med. Chem., 33, 999–1009
Arai, T., Koyama, Y., Suenaga, T. and Honda, H. (1962). Ascomycin, an antifungal antibiotic. J. Antibiotics, 15, 231–232
Bartlett, P. A., Shea, G. T., Telfer, S. J. and Waterman, S. (1989). CAVEAT: A program to facilitate the structure-derived design of biologically active molecules. In Roberts, S. M. (Ed.), Molecular Recognition: Chemical and Biological Problems. Royal Society of Chemistry, London, Vol. 78, pp. 182–196
Bax, A., Clore, G. M. and Gronenborn, A. M. (1990). Proton-proton correlation via isotropic mixing of carbon-13 magnetization, a new three-dimensional approach for assigning proton and carbon-13 spectra of carbon-13-enriched proteins. J. Magn. Reson., 88, 425–431
Bax, A. and Ikura, M. (1991). An efficient 3D NMR technique for correlating the proton and nitrogen-15 backbone amide resonances with the α-carbon of the preceding residue in uniformly nitrogen-15/carbon-13 enriched proteins. J. Biomol NMR, 1, 99–104
Bierer, B. E., Mattila, P. S., Standaert, R. F., Herzenberg, L. A., Burakoff, S. J., Crabtree, G. and Schreiber, S. L. (1990a). Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc. Natl Acad. Sci. USA, 87, 9231–9235
Bierer, B. E., Somers, P. K., Wandless, T. J., Burakoff, S. J. and Schreiber, S. L. (1990b). Probing immunosuppressant action with a nonnatural immunophilin ligand. Science, 250, 556–559
Brünger, A. T. (1990). XPLOR Manual, Version 2.1
Clore, G. M., Bax, A., Wingfield, P. T. and Gronenborn, A. M. (1990). Identification and localization of bound internal water in the solution structure of interleukin 1β by heteronuclear three-dimensional 1H rotating-frame Overhauser 15N-1H multiple quantum coherence NMR spectroscopy. Biochemistry, 29, 5671–5676
Clore, G. M., Kay, L. E., Bax, A. and Gronenborn, A. M. (1991). Four-dimensional 13C/13C-edited nuclear Overhauser enhancement spectroscopy of a protein in solution: Application to interleukin 1β. Biochemistry, 30, 12–18
Dumont, F. J., Melino, M. R., Staruch, M. J., Koprak, S. L., Fischer, P. A. and Sigal, N. H. (1990a). The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J. Immunol., 144, 1418–1424
Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. and Sigal, N. H. (1990b). Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J. Immunol., 144, 251–258
Durette, P. L., Boger, J., Dumont, F., Firestone, R., Frankshun, R. A., Koprak, S. L., Lin, C. S., Melino, M. R., Pessolano, A. A., Pisano, J., Schmidt, J. A., Sigal, N. H., Staruch, M. J. and Witzel, B. E. (1988). A study of the correlation between cyclophilin binding and in vitro immunosuppressive activity of cyclosporine A and analogues. Transplant. Proc., 20, 51–57
Emmel, E. A., Verweij, C. L., Durand, D. B., Higgins, K. M., Lacy, E. and Crabtree, G. R. (1989). Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science, 246, 1617–1620
Fesik, S. W. (1989). Approaches to drug design using nuclear magnetic resonance spectroscopy. In Perun, T. J. and Propst, C. L. (Eds), Computer-Aided Drug Design. Methods and Applications. Marcel Dekker, New York, pp. 133–184
Fesik, S. W. (1991). NMR studies of molecular complexes as a tool in drug design. J. Med. Chem., 34, 2937–2945
Fesik, S. W., Eaton, H. L., Olejniczak, E. T., Zuiderweg, E. R. P., McIntosh, L. P. and Dahlquist, F. W. (1990a). 2D and 3D NMR spectroscopy employing 13C-13C magnetization transfer by isotropic mixing. Spin system identification in large proteins. J. Am. Chem. Soc., 112, 886–888
Fesik, S. W., Gampe, R. T. J., Eaton, H. L., Gemmecker, G., Olejniczak, E. T., Neri, P., Holzman, T. F., Egan, D. A., Edalji, R., Helfrich, R., Hochlowski, J. and Jackson, M. (1991a). NMR studies of [U-13C]Cyclosporin A bound to cyclophilin. Bound conformation and portions of cyclosporin involved in binding. Biochemistry, 30, 6574–6583
Fesik, S. W., Gampe, R. T., Jr., Holzman, T. F., Egan, D. A., Edalji, R., Luly, J. R., Simmer, R., Helfrich, R., Kishore, V. and Rich, D. H. (1990b). Isotope-edited NMR of cyclosporin A bound to cyclophilin: Evidence for a trans 9,10 amide bond. Science, 250, 1406–1409
Fesik, S. W., Gemmecker, G., Olejniczak, E. T. and Petros, A. M. (1991b). Identification of solvent-exposed regions of enzyme-bound ligands by nuclear magnetic resonance. J. Am. Chem. Soc., 113, 7080–7081
Fesik, S. W., Luly, J. R., Erickson, J. W. and Abad, Z. C. (1988). Isotope-edited proton NMR study on the structure of a pepsin/inhibitor complex. Biochemistry, 27, 8297–8301
Fesik, S. W., Neri, P., Meadows, R., Olejniczak, E. T. and Gemmecker, G. (1992). A model of the cyclophilin/cyclosporin A (CsA) complex from NMR and X-ray data suggests that CsA binds as a transition-state analogue. J. Am. Chem. Soc., 114, 3165–3166
Fesik, S. W. and Zuiderweg, E. R. P. (1988). Heteronuclear three dimensional NMR spectroscopy. A strategy for the simplification of homonuclear two dimensional NMR spectra. J. Magn. Reson., 78, 588–593
Fesik, S. W. and Zuiderweg, E. R. P. (1989). An approach for studying the active site of enzyme/inhibitor complexes using deuterated ligands and 2D NOE difference spectroscopy. J. Am. Chem. Soc., 111, 5013–5015
Fesik, S. W. and Zuiderweg, E. R. P. (1990). Heteronuclear three-dimensional NMR spectroscopy of isotopically labelled biological macromolecules. Quart. Rev. Biophys., 23, 97–131
Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. and Schmid, F. X. (1989). Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature, 337, 476–478
Galat, A., Lane, W. S., Standaert, R. F. and Schreiber, S. L. (1992). A rapamycin-selective 25-kDa immunophilin. Biochemistry, 31, 2427–2434
Gemmecker, G. and Fesik, S. W. (1991). A method of measuring proton-proton coupling constants in carbon-13-labeled molecules. J. Magn. Reson., 95, 208–213
Gemmecker, G., Olejniczak, E. T. and Fesik, S. W. (1992). An improved method for selectively observing protons attached to 12C in the presence of 1H-13C spin pairs. J. Magn. Reson., 96, 199–204
Goodford, P. J. (1985). A computation procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem., 28, 849–857
Handschumacher, R. E., Harding, M. W., Rice, J., Drugge, R. J. and Speicher, D. W. (1984). Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science, 226, 544–547
Harding, M. W., Galat, A., Uehling, D. E. and Schreiber, S. L. (1989). A receptor for the immunosuppressant FK-506 is a cis-trans peptidyl-propyl isomerase. Nature, 341, 758–760
Hatanka, H., Kino, T., Miyata, S., Inamura, N., Kuroka, A., Goto, T., Tanaka, H. and Okuhara, M. (1988). FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. II. Fermentation, isolation and physico-chemical and biological characteristics. J. Antibiot., 41, 1592–1601
Ikura, M. and Bax, A. (1992). Isotope-filtered 2D NMR of a protein-peptide complex: study of a skeletal muscle myosin light chain kinase fragment bound to calmodulin. J. Am. Chem. Soc., 114, 2433–2440
Kahan, B. B. (1989). Cyclosporine. New Engl. J. Med., 321, 1725–1738
Kallen, J., Spitzfaden, C., Zurini, M. G., Wider, G., Widmer, H., Wuthrich, K. and Walkinshaw, M. D. (1991). Structure of human cyclophilin and its binding site for cyclosporin A determined by X-ray crystallography and NMR spectroscopy. Nature, 353, 276–279
Kallen, J. and Walkinshaw, M. D. (1992). The x-ray structure of a tetrapeptide bound to the active site of human cyclophilin A. FEBS Lett., 300, 286–290
Karuso, P., Kessler, H. and Mierke, D. F. (1990). Solution structure of FK-506 from nuclear magnetic resonance and molecular dynamics. J. Am. Chem. Soc., 112, 9434–9436
Kay, L. E. and Bax, A. (1990). New methods for the measurement of NH-CαH coupling constants in 15N-labeled proteins. J. Magn. Reson., 86, 110–126
Kay, L. E., Clore, G. M., Bax, A. and Gronenborn, A. M. (1990a). Four-dimensional heteronuclear triple-resonance NMR spectroscopy of interleukin-1β in solution. Science, 249, 411–414
Kay, L. E., Ikura, M. and Bax, A. (1990b). Proton-proton correlation via carbon-carbon couplings: A three-dimensional NMR approach for the assignment of aliphatic resonances in proteins labeled with carbon-13. J. Am. Chem. Soc., 112, 888–889
Kay, L. E., Ikura, M., Tschudin, R. and Bax, A. (1990c). Three-dimensional triple-resonance NMR spectroscopy of isotopically enriched proteins. J. Magn. Reson., 89, 496–514
Ke, H., Zydowsky, L. D., Liu, J. and Walsh, C. T. (1991). Crystal structure of recombinant human T-cell cyclophilin A at 2.5 Å resolution. Proc. Natl Acad. Sci. USA, 88, 9483–9487
Kessler, H., Köck, M., Wein, T. and Geherke, M. (1990). Reinvestigation of the conformation of cyclosporin A in chloroform. Helv. Chim. Acta, 72, 1818–1832
Kuntz, I. D., Blaney, J. M., Oatley, S. J., Langridge, R. and Ferrin, T. E. (1982). A geometric approach to macromolecule-ligand interactions. J. Mol. Biol., 161, 269–288
Liu, J., Albers, M. W., Wandless, T. J., Luan, S., Alberg, D. G., Belshaw, P. J., Cohen, P., MacKintosh, C., Klee, C. B. and Schreiber, S. L. (1992). Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry, 31, 3896–3901
Liu, J., Farmer, J. D., Jr., Lane, W. S., Friedman, J., Weissman, I. and Schreiber, S. L. (1991). Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK-506 complexes. Cell, 66, 807–815
Loosli, H. R., Kessler, H., Oschkinat, H., Weber, H. P., Petcher, T. J. and Widmer, T. J. (1985). The conformation of cyclosporin A in the crystal and in solution. Helv. Chim. Acta, 68, 682–704
McIntosh, L. P., Wand, A. J., Lowry, D. F., Redfield, A. G. and Dahlquist, F. W. (1990). Assignment of the backbone 1H and 15N NMR resonances of bacteriophage T4 lysozyme. Biochemistry, 29, 6341–6362
Marion, D., Driscoll, P. C., Kay, L. E., Wingfield, P. T., Bax, A., Gronenborn, A. M. and Clore, G. M. (1989a). Overcoming the overlap problem in the assignment of 1H-NMR spectra of larger proteins by use of three-dimensional heteronuclear 1H-15N Hartmann-Hahn multiple quantum coherence and nuclear Overhauser-multiple quantum coherence spectroscopy. Biochemistry, 28, 6150–6156
Marion, D., Kay, L. E., Sparks, S. W., Torchia, D. A. and Bax, A. (1989b). Three-dimensional heteronuclear NMR of 15N-labeled proteins. J. Am. Chem. Soc., 111, 1515–1517
Meadows, R. P., Nettesheim, D. G., Xu, R. X., Olejniczak, E. T., Petros, A. M., Holzman, T. F., Severin, J., Gubbins, E., Smith, H. and Fesik, S. W. (1993). Three-dimensional structure of the FK506 binding protein/ascomycin complex in solution by heteronuclear three- and four-dimensional NMR. Biochemistry, 32, 757–765
Michnick, S. W., Rosen, M. K., Wandless, T. J., Karplus, M. and Schreiber, S. L. (1991). Solution structure of FKBP, a rotamase enzyme and receptor for FK506 and rapamycin. Science, 252, 836–839
Mierke, D. F., Schmieder, P., Karuso, P. and Kessler, H. (1991). Conformational analysis of the cis- and trans-isomers of FK-506 by NMR and molecular dynamics. Helv. Chim. Acta, 74, 1027–1047
Montelione, G. T., Winkler, M. E., Rauenbuehler, P. and Wagner, G. (1989). Accurate measurements of long-range heteronuclear coupling constants from homonuclear 2D NMR spectra of isotope-enriched proteins. J. Magn. Resort., 82, 198–204
Moore, J. M., Peattie, D. A., Fitzgibbon, M. J. and Thomson, J. A. (1991). Solution structure of the major binding protein for the immunosuppressant FK506. Nature, 351, 248–250
Neri, P., Meadows, R., Gemmecker, G., Olejniczak, E., Nettesheim, D., Logan, T., Simmer, R., Helfrich, R., Holzman, T., Severin, J. and Fesik, S. (1991). 1H, 13C and 15N backbone assignments of cyclophilin when bound to cyclosporin A (CsA) and preliminary structural characterization of the CsA binding site. FEBS Lett., 294, 81–88
Neri, D., Szyperski, T., Otting, G., Senn, H. and Wüthrich, K. (1989). Stereo-specific nuclear magnetic resonance assignments of the methyl groups of valine and leucine in the DNA-binding domain of the 434 repressor by biosynthetically directed fractional 13C labeling. Biochemistry, 28, 7510–7516
Nilges, M., Clore, G. M. and Gronenborn, A. M. (1988). Determination of three-dimensional structures of proteins from interproton distance data by hybrid distance geometry-dynamical simulated annealing calculations. FEBS Lett., 229, 317–324
Petros, A. M., Gampe Jr., R. T., Gemmecker, G., Neri, P., Holzman, T. F., Edalji, R., Hochlowski, J., Jackson, M., McAlpine, J., Luly, J. R., Pilot-Matias, T., Pratt, S. and Fesik, S. W. (1991). NMR studies of an FK-506 analog, [U-13C]ascomycin, bound to FKBP: Conformation and regions of ascomycin involved in binding. J. Med. Chem., 34, 2925–2928
Petros, A. M., Gemmecker, G., Neri, P., Olejniczak, E. T., Nettesheim, D., Xu, R. X., Gubbins, E. G., Smith, H. and Fesik, S. W. (1992a). NMR studies of an FK-506 analog, [U-13C] ascomycin, bound to FK-506-binding protein. J. Med. Chem., 35, 2467–2473
Petros, A. M., Kawai, M., Luly, J. R. and Fesik, S. W. (1992b). Conformation of two non-immunosuppressive FK506 analogs when bound to FKBP by isotope-filtered NMR. FEBS Lett., 308, 309–314
Petros, A. M., Neri, P. and Fesik, S. W. (1992c). Identification of solvent-exposed regions of an FK-506 analog, ascomycin, bound to FKBP using a paramagnetic probe. J. Biomol. NMR, 2, 11–18
Quesniaux, V. F. J., Schreier, M. H., Wenger, R. M., Hiestand, P. C., Harding, M. W. and Van Regenmortel, M. H. V. (1987). Cyclophilin binds to the region of cyclosporine involved in its immunosuppressive activity. Eur. J. Immunol., 17, 1359–1365
Quesniaux, V. F. J., Schreier, M. H., Wenger, R. M., Hiestand, P. C., Harding, M. W. and Van Regenmortel, M. H. V. (1988). Molecular characteristics of cyclophilin-cyclosporin interaction. Transplantation, 46, 23S–27S
Rich, D. H., Sun, C.-Q., Guillaume, D., Dunlap, B., Evans, D. A. and Weber, A. (1989). Synthesis, biological activity, and conformational analysis of 2S,3R,4S-MeBmtl-cyclosporin, a novel 1-position epimer of cyclosporin A. J. Med. Chem., 32, 1982–1987
Schreiber, S. L. (1991). Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science, 251, 283–287
Seeholzer, S. H., Cohn, M., Putkey, J. A., Means, A. R. and Crespi, H. L. (1986). NMR studies of a complex of deuterated calmodulin with melittin. Proc. Natl Acad. Sci. USA, 83, 3634–3638
Senn, H., Werner, B., Messerle, B., Weber, C., Traber, R. and Wüthrich, K. (1989). Stereospecific assignment of the methyl 1H NMR lines of valine and leucine in polypeptides by nonrandom 13C labelling. FEBS Lett., 249, 113–118
Siekierka, J. J., Hung, S. H. Y., Poe, M., Lin, C. S. and Sigal, N. H. (1989). A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature, 341, 755–757
Sigal, N. H., Dumont, F., Siekierka, J. J., Peterson, L., Rich, D. H., Dunlap, B. E., Staruch, M. J., Melino, M. R., Koprack, S. L., Williams, D., Witzel, B. and Pisano, J. M. (1991). Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? J. Exptl Med., 173, 619–628
Spera, S. and Bax, A. (1991). Empirical correlation between protein backbone conformation and Cα and Cβ13C nuclear magnetic resonance chemical shifts. J. Am. Chem. Soc., 113, 5490–5492
Spitzfaden, C., Weber, H.-P., Braun, W., Kallen, J., Wider, G., Widmer, H., Walkinshaw, M. D. and Wüthrich, K. (1992). Cyclosporin A-cyclophilin complex formation. A model based on x-ray and NMR data. FEBS Lett., 300, 291–300
Taga, T., Tanaka, H., Goto, T. and Tada, S. (1987). Structure of a new macrocylic antibiotic. Acta Crystallog., C43, 751–753
Takahashi, N., Hayano, T. and Suzuki, M. (1989). Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature, 337, 473–475
Theriault, Y., Logan, T. M., Meadows, R., Yu, L., Olejniczak, E. T., Holzman, T., Simmer, R. L. and Fesik, S. W. (1993). Solution structure of the cyclosporin A/cyclophilin complex by NMR. Nature, 361, 88–91
Thomson, A. W. (1990). FK-506: profile of an important new immunosuppressant. Transplantation Rev., 4, 1–13
Van Drie, J. H., Weininger, D. and Martin, Y. C. (1989). ALADDIN: An integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric, steric, and substructure searching of three-dimensional molecular structures. J. Comput.-aided Des. 3, 225–251
Van Duyne, G. D., Standaert, R. F., Karplus, P. A., Schreiber, S. L. and Clardy, J. (1991a). Atomic structure of FKBP-FK-506, an immunophilin-immunosuppressant complex. Science, 252, 839–842
Van Duyne, G. D., Standaert, R. F., Schreiber, S. L. and Clardy, J. (1991b). Atomic structure of the rapamycin human immunophilin FKBP-12 complex. J. Am. Chem. Soc., 113, 7433–7434
Wandless, T. J., Michnick, S. W., Rosen, M. K., Karplus, M. and Schreiber, S. L. (1991). FK506 and rapamycin binding to FKBP: common elements in immunophilin-ligand complexation. J. Am. Chem. Soc., 113, 2339–2341
Weber, C., Wider, G., von Freyberg, B., Traber, R., Braun, W., Widmer, H. and Wüthrich, K. (1991). The NMR structure of cyclosporin A bound to cyclophilin in aqueous solution. Biochemistry, 30, 6563–6574
Wenger, R. M. (1986). Cyclosporine and analogues: Structural requirements for immunosuppressive activity. Transplant. Proc., 18, 213–218
Wider, G., Weber, C., Traber, R., Widmer, H. and Wüthrich, K. (1990). Use of a double-half-filter in two-dimensional 1H nuclear magnetic resonance studies of receptor-bound cyclosporin. J. Am. Chem. Soc., 112, 9015–9016
Wüthrich, K. (1986). NMR of Proteins and Nucleic Acids. Wiley, New York
Wüthrich, K., Spitzfaden, C., Memmert, K., Widmer, H. and Wider, G. (1991). Protein secondary structure determination by NMR. Application with recombinant human cyclophilin. FEBS Lett., 285, 237–247
Xu, R. X., Meadows, R. and Fesik, S. W. (1993). Heteronuclear 3D NMR studies of water bound to an FK506 binding protein/immunosuppressant complex. Biochemistry, 32, 2473–2480
Xu, R. X., Nettesheim, D., Olejniczak, E. T., Meadows, R., Gemmecker, G. and Fesik, S. W. (1992a). 1H, 13C and 15C assignments and secondary structure of the FK506 binding protein when bound to ascomycin. Biopolymers, 33, 535–550
Xu, R. X., Olejniczak, E. T. and Fesik, S. W. (1992b). Stereospecific assignments and χ1 rotamers for FKBP when bound to ascomycin from 3JHαH,β and 3JN,Hβ coupling constants. FEBS Lett., 305, 137–143
Zuiderweg, E. R. P., Petros, A. M., Fesik, S. W. and Olejniczak, E. T. (1991). Four-dimensional [13C, 1H, 13C, 1H]HMQC-NOE-HMQC NMR spectroscopy: Resolving tertiary NOE distance constraints in the spectra of larger proteins. J. Am. Chem. Soc., 113, 370–372
Editor information
Editors and Affiliations
Copyright information
© 1993 The contributors
About this chapter
Cite this chapter
Fesik, S.W., Neri, P. (1993). Multidimensional NMR Studies of Immunosuppressant/Immunophilin Complexes. In: Clore, G.M., Gronenborn, A.M. (eds) NMR of Proteins. Topics in Molecular and Structural Biology. Palgrave, London. https://doi.org/10.1007/978-1-349-12749-8_4
Download citation
DOI: https://doi.org/10.1007/978-1-349-12749-8_4
Publisher Name: Palgrave, London
Print ISBN: 978-1-349-12751-1
Online ISBN: 978-1-349-12749-8
eBook Packages: EngineeringEngineering (R0)