Binding, gating, affinity and efficacy: The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors

British Journal of Pharmacology

Volumn 125, Issue 5, 1998, Pages 923-947

  Colquhoun, David ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Affinity; Binding; Efficacy; G protein coupled receptors; Gating; Ion channels; Mutation studies; Receptor theory; Receptors; Single channels

Indexed keywords

CELL SURFACE RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; ION CHANNEL; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; MUTANT PROTEIN; NICOTINIC RECEPTOR; RECEPTOR;

ALLOSTERISM; ANIMAL; CHANNEL GATING; DOSE RESPONSE; DRUG POTENTIATION; GENETICS; HUMAN; METABOLISM; NUCLEOTIDE SEQUENCE; PROTEIN CONFORMATION; REVIEW; STRUCTURE ACTIVITY RELATION; BINDING SITE; CONFORMATIONAL TRANSITION; PRIORITY JOURNAL; RECEPTOR AFFINITY; RECEPTOR BINDING;

ALLOSTERIC REGULATION; ANIMALS; DNA MUTATIONAL ANALYSIS; DOSE-RESPONSE RELATIONSHIP, DRUG; GTP-BINDING PROTEINS; HUMANS; ION CHANNEL GATING; ION CHANNELS; PROTEIN CONFORMATION; RECEPTORS, CELL SURFACE; RECEPTORS, N-METHYL-D-ASPARTATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032199006     PISSN: 00071188     EISSN: None     Source Type: Journal    
DOI: 10.1038/sj.bjp.0702164     Document Type: Article

References (111)

1. AKK, G. SINE, S. & AUERBACH, A. (1996). Binding sites contribute unequally to the gating of mouse nicotinic α-D200N acetylcholine receptors. J. Physiol. (Lond.), 496, 185-196.
2. ANSON, L.C., CHEN, P.E., WYLLIE, D.J.A., COLQUHOUN, D. & SCHOEPFER, R. (1998). Identification of amino acid residues of the NR2A subunit which control glutamate potency in recombinant NR1/NR2A NMDA receptors. Journal of Neuroscience, 18, 581-589.
3. ARUNLAKSHANA, O. & SCHILD, H. O. (1959). Some quantitative uses of drug antagonists. British Journal of Pharmacology and Chemotherapy, 14, 47-58.
4. BÉHÉ, P., STERN, P., WYLLIE, D.J.A., NASSAR, M., SCHOEPFER, R. & COLQUHOUN, D. (1995). Determination of the NMDA NR1 subunit copy number in recombinant NMDA receptors. Proceedings of the Royal Society London B, 262, 205-213.
5. BERTIN, B., FREISSMUTH, M., JOCKERS, R., STROSBERG, A.D. & MARULLO, S. (1995) Cellular signaling by an agonist-activated receptor/Gs alpha fusion protein. Proc. Natl. Acad. Sci. USA, 91, 8827-8831.
6. BIRDSALL, N.J.M., BURGEN, A.S.V. & HULME, E.C. (1978). The Binding of agonists to brain muscarinic receptors. Molecular Pharmacology, 14, 723-736.
7. BIRNBAUMER, L.G., SWARTZ, T.L., ABRAMOWITZ, J., MINTZ, P.W., & IYENGAR, R. (1980) Transient and steady state kinetics of the interaction of guanyl nucleotides with the adenylyl cyclase system from rat liver plasma membranes. Interpretation in terms of a simple two state model. J. Biol. Chem., 255, 3542-3551.
8. BLACK, J.W. & LEFF, P. (1983). Operational models of pharmacological agonism. Proceedings of the Royal Society London B, 220, 141-162.
9. BOURNE, H.R. (1997). How receptors talk to trimeric G proteins. Current Opinion in Cell Biology, 9, 134-142.
10. BURSTEIN, E.S., SPALDING, T.A. & BRANN, M. R. (1997). Pharmacology of muscarinic receptor subtypes constitutively activated by G proteins. Mol. Pharmacol., 51, 312-319.
11. i proteins. Journal of Biological Chemistry, 273, 10367-10375.
12. CAMPOS-CARO, A., SALA, S., BALLESTA J.J., VICENTE-AGULLO, F., CRIADO, M. & SALA, F. (1996). A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors. Proc. Natl. Acad. Sci. USA, 93, 6118-6123.
13. CHANGEUX, J.-P. (1993). Allosteric proteins: from regulatory enzymes to receptors. BioEssays, 15, 625-634.
14. CHEN, J., ZHANG, Y., AKK, G., SINE, S. & AUERBACH, A. (1995). Activation kinetics of recombinant mouse nicotinic acetylcholine receptors: Mutations of α-subunit tyrosine 190 affect both binding and gating. Biophysical Journal, 69, 849-859.
15. CHIARA, D.C., MIDDLETON, R.E. & COHEN, J. B. (1998). Identification of tryptophan 55 as the primary site of [3H]nicotine photoincorporation in the Γ-subunit of the Torpedo nicotinic acetylcholine receptor. FEBS Letters, 423, 223-226.
16. CLAPHAM, D.E. (1996). The G-protein nanomachine. Nature, 379, 297-299.
17. CLARKE, W.P. & BOND, R.A. (1998). The elusive nature of intrinsic efficacy Trends in Pharmacological Sciences, 19, 270-276.
18. COLQUHOUN, D. (1971). Lectures on Biostatistics, Clarendon Press, Oxford.
19. COLQUHOUN, D. (1973). The relation between classical and cooperative models for drug action. In Drug Receptors, Rang, H.P., pp. 149-182, Macmillan Press, London.
20. COLQUHOUN, D. (1987). Affinity, efficacy and receptor classification: is the classical theory still useful? In: Perspectives on hormone receptor classification. Ed. Black, J.W.; Jenkinson, D.H. & Gerskowitch, V.P, pp 103-104 New York, Alan R.Liss Inc., New York, 103-114.
21. COLQUHOUN, D. & FARRANT, M. (1993). The Binding Issue. Nature, 366, 510-511.
22. COLQUHOUN, D., HAWKES, A.G., MERLUSHKIN, A. & EDMONDS, B. (1997). Properties of single ion channel currents elicited by a pulse of agonist concentration or voltage. Philosophical Transactions of the Royal Society London (Physical Sciences), A 355, 1743-1786.
23. COLQUHOUN, D., HAWKES, A.G. & SRODZINSKI, K. (1996). Joint distributions of apparent open times and shut times of single ion channels and the maximum likelihood fitting of mechanisms. Philosophical Transactions of the Royal Society London, A 354, 2555-2590.
24. COLQUHOUN, D., JONAS, P. & SAKMANN, B. (1992). Action of brief pulses of glutamate on AMPA/kainate receptors in patches from different neurones of rat hippocampal slices. Journal of Physiology (London), 458, 261-287.
25. COLQUHOUN, D. & OGDEN, D.C. (1988). Activation of ion channels in the frog end-plate by high concentrations of acetylcholine. Journal of Physiology (London), 395, 131-159.
26. COLQUHOUN, D. & SAKMANN, B. (1981). Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels. Nature, 294, 464-466.
27. COLQUHOUN, D. & SAKMANN, B. (1985). Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. Journal of Physiology (London), 369, 501-557.
28. COLQUHOUN, D. & SAKMANN, B. (1998). From muscle endplate to brain synapses: A short history of synapses and agonist-activated ion channels. Neuron, 20, 381-387.
29. COLQUHOUN, D. & SIGWORTH, F.J. (1995). Analysis of single ion channel data. In Single channel recording, ed. Sakmann, B. & Neher, E. pp. 483-587, New York, Plenum Press.
30. COSTA, T. & HERZ, A. (1989). Antagonists with negative intrinsic activity at opioid receptors coupled to GTP-binding proteins. Proc. Natl. Acad. Sci. USA, 86, 7321-7325.
31. COSTA, T., OGINO, Y., MUNSON, P.J., ONARAN, H.O. & RODBARD, D. (1992). Drug Efficacy at guanine nucleotide-binding regulatory protein-linked receptors: Thermodynamic interpretation of negative antagonism and of receptor activity in the absence of ligand. Molecular Pharmacology 41, 549-560.
32. DEL CASTILLO, J., KATZ, B. (1957). Interaction at end-plate receptors between different choline derivatives. Proc. Roy. Soc. Lond. B., 146, 369-381.
33. DE LEAN, A, STADEL, J.M. & LEFKOWITZ, R. (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J. Biol. Chem., 255, 7108-7117.
34. DOYLE, D.A., CABRAL, J.M., PFUETZNER, R.A., KUO, A., GULBIS, J.M., COHEN, S.L., CHAIT, B.T. & MACKINNON, R. (1998). The Structure of the Potassium channel: Molecular Basis of K + Conduction and Selectivity. Science, 280, 69-77.
35. EDELSTEIN, S.J. (1975). Cooperative interactions of hemoglobin. Annual Review of Biochemistry, 44, 209-232.
36. EDMONDS, B., GIBB, A. J. & COLQUHOUN, D. (1995). Mechanisms of activation of muscle nicotinic acetylcholine receptors, and the time course of endplate currents. Annual Review of Physiology, 57, 469-493.
37. EDSALL, J.T. & WYMAN, J. (1958). Biophysical Chemistry. Academic Press, New York.
38. FRANKE, C., PARNAS, H., HOVAV, G. & DUDEL, J. (1993). A molecular scheme for the reaction between acetylcholine and nicotinic channels. Biophysical Journal, 64, 339-356.
39. FURCHGOTT, R.F. (1966). The use of ζ-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. Advances in Drug Research, 3, 21-55.
40. GARDNER, P., OGDEN, D.C., COLQUHOUN, D. (1984). Conductances of single ion channels opened by nicotinic agonists are indistinguishable. Nature, 309, 160-162.
41. GETHER, U., LIN, S. & KOBILKA, B.K. (1995). Fluorescent labeling of purified β2 adrenergic receptor. Journal of Biological Chemistry, 270, 28268-28275.
42. GIBB, A.J. & COLQUHOUN, D. (1992). Activation of N-Methyl-D-Aspartate receptors by L-glutamate in cells dissociated from adult rat hippocampus. Journal of Physiology (London), 456, 143-179.
43. HILL, A.V. (1909). The mode of action of nicotine and curari determined by the form of the contraction curve and the method of temperature coefficients. J. Physiol. (Lond.), 39, 361-373.
44. HILLE, B. (1992). Ionic Channels of Excitable Membranes. 2nd ed. Sinauer Associates Inc., Sunderland, Mass.
45. HOLLENBERG, M.D. (1991). Structure-activity relationships for transmembrane signaling: the receptor's turn. FASEB J., 5, 178-186.
46. HOWE, J.R., CULL-CANDY, S.G. & COLQUHOUN, D. (1991). Currents through single glutamate-receptor channels in outside-out patches from rat cerebellar granule cells. Journal of Physiology (London), 432, 143-202.
47. HULME, E.C., BIRDSALL, N.J.M., BURGEN, A.S.V. & MEHTA, P. (1978). The binding of antagonists to brain muscarinic receptors. Molecular Pharmacology, 14, 737-750.
48. HULME, E.C., BIRDSALL, N.J.M. & BUCKLEY, N.J. (1990). Muscarinic receptor subtypes. Annu. Rev. Pharmacol. Toxicol., 30, 633-673.
49. IMOTO, K., METHFESSEL, C., SAKMANN, B., MISHINA, M., MORI, Y., KONNO, T., FUKUDA, K., KURASAKI, M., BUJO, H., FUJITA, Y. & NUMA, S. (1986). Location of a delta-subunit region determining ion transport through the acetylcholine receptor channel. Nature, 324, 670-674.
50. IMOTO, K., BUSCH, C., SAKMANN, B., MISHINA, M., KONNO, T., NAKAI, J., BUJO, H., MORI, Y., FUKUDA, K. & NUMA, S. (1988). Rings of negatively charged amino acids as determinants of acetylcholine receptor channel conductance. Nature, 335, 645-648
51. JACKSON, M.B. (1994). Single channel currents in the nicotinic acetylcholine receptor: a direct demonstration of allosteric transitions. Trends Biol. Sci., 19, 396-399.
52. JENKINSON, D.H. (1989). Finding affinity constants for agonists by the irreversible antagonist method. Trends Pharmacol. Sci., 10, 16-17.
53. JENKINSON, D.H.J. (1996). Classical Approaches to the Study of Drug-Receptor Interactions. In: Textbook of Receptor Pharmacology. 1st ed. ed. Foreman, J.C., Johansen T. CRC Press, Boca Raton, Florida, pp. 3-62.
54. KARLIN, A. (1967). On the application of "a Plausible Model" of allosteric proteins to the receptor for acetylcholine. Journal of Theoretical Biology 16, 306-320.
55. KARLIN, A. & AKABAS, M.H. (1995). Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron, 15, 1231-1244.
56. KENAKIN, T. (1997a). A Pharmacologic Analysis of Drug-Receptor Interaction. 3rd ed. Lippincott-Raven, Philadelphia. 491 pages.
57. KENAKIN, T. (1997b). Agonist-specific receptor conformations. Trends in Pharmacological Sciences, 18, 416-417.
58. 1B-adrenergic receptor by all amino acid substitutions at a single site. Journal of Biological Chemistry, 267, 1430-1433.
59. LAUBE, B., HIRAI, H., STURGESS, M., BETZ, H. & KUHSE, J. (1997). Molecular determinants of agonist discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit. Neuron, 18, 493-503.
60. LEFF, P. & DOUGAL, I. G. (1993). Further concerns over Cheng-Prusoff analysis. Trends in Pharmacological Sciences, 14, 110-112.
61. LEFF, P. & SCARAMELLINI, C. (1998). Promiscuity, pre-coupling and instability. Trends in Pharmacological Sciences, 19, 13.
62. LEFF, P., SCARAMELLINI, C., LAW, C. & MCKECHNIE, K. (1997). A three-state receptor model of agonist action. Trends in Neurosciences, 18, 355-362.
63. LEFKOWITZ, R.J., COTECCHIA, S., SAMAMMA, P. & COSTA, T. (1993). Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends in Pharmacological Sciences, 14, 303-307.
64. 1 (K276E), expressed in Xenopus oocytes. Journal of Physiology (London), 507, 25-40.
65. LIU, D.T., TIBBS, G.R., PAOLETTI, P., SIEGELBAUM, S.A. (1998). Constraining ligand-binding site stoichiometry suggests that a cyclic nucleotide-gated channel is composed of two functional dimers. Neuron, 21, 235-248.
66. LYNCH, J.W., RAJENDRA, S., PIERCE, K.D., HANDFORD, C.A., BARRY, P.H. & SCHOFIELD, P.R. (1997). Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel. EMBO Journal, 16, 110-120.
67. MACONOCHIE, D.J. & STEINBACH, J.-H. (1998). The channel opening rate of adult- and fetal-type mouse muscle nicotinic receptors activated by acetylcholine. Journal of Physiology (London), 506, 53-72.
68. MIDDLETON, R.E. & COHEN, J.B. (1991). Mapping of the acetylcholine binding site of the nicotinic acetylcholine receptor: [3H]nicotine as an agonist photoaffinity label. Biochemistry, 30, 6987-6997.
69. MILLER, C. (1997). Cuddling up to channel activation. Nature, 389, 328-329.
70. MONOD, J. & JACOB, F. (1961). General conclusions: Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harbor Symposia on Quantitative Biology, 26, 389-401.
71. MONOD, J., CHANGEUX, J.-P. & JACOB, F. (1963). Allosteric proteins and cellular control systems. Journal of Molecular Biology, 6, 306-329.
72. MONOD, J., WYMAN, J. & CHANGEUX, J.-P. (1965). On the nature of allosteric transitions: A plausible model. J. Mol. Biol., 12, 88-118.
73. MOREY, T.E., BELARDINELLI, L. & DENNIS, D. M. (1998). Validation of Furchgott's method to determine agonist-dependent A1-adenosine receptor reserve in guinea-pig atrium. British Journal of Pharmacology, 123, 1425-1433.
74. NARGEOT, J., NERBONNE, J.M., ENGELS, J. & LESTER, H.A. (1983). Time course of the increase in the myocardial slow inward current after a photochemically generated concentration jump of intracellular cAMP. Proceedings of the National Academy of Sciences, USA, 80, 2395-2399.
75. PARMENTIER, M.-L., JOLY, C., RESTITUITO, S., BOCKAERT, J., GRAU, Y. & PIN, J.-P. (1998). The G protein-coupling profile of metabotropic glutamate receptors, as determined with exogenous G proteins, is independent of their ligand recognition domain. Molecular Pharmacology, 53, 778-786.
76. POTT, L. (1979). On the time course of the acetylcholine-induced hyperpolarizationin quiescent guinea-pig atria. Pfluger's Archiv., 380, 71-77.
77. QIN, F., AUERBACH, A. & SACHS, F. (1997). Maximum likelihood estimation of aggregated Markov processes. Proceedings of the Royal Society London B, 264, 375-383.
78. RAJENDRA, S., LYNCH, J.W., PIERCE, K.D., FRENCH, C.R., BARRY, P.H. & SCHOFIELD, P.R. (1995). Mutation of an arginine residue in the human glycine receptor transforms ά-alanine and taurine from agonists into competitive antagonists. Neuron, 14, 169-175.
79. RAJENDRA, S. & SCHOFIELD, P.R. (1995). Molecular mechanisms of inherited startle syndromes. Trends in Neurosciences, 18, 80-82.
80. ROSENMUND, C., STERN-BACH, Y. & STEVENS, C.F. (1998). The tetrameric structure of a glutamate receptor channel. Science, 280, 1596-1599.
81. ROSS, E., M. (1996). Pharmacodynamics. In The Pharmacological Basis of Therapeutics, eds. Hardman. J.G., Limbird, L.E., Molinoff,. P.B., Ruddon, R.W. & Gilman, A.G. 9th edition, McGraw Hill.
82. RUIZ, M. & KARPEN, J.W. (1997). Single cyclic nucleotide-gated channels locked in different ligand-bound states. Nature, 389, 389-392.
83. 2-adrenergic receptor: extending the ternary complex model. J. Biol. Chem., 268, 4625-4636.
84. SCHILD, H.O. (1949). pAx and competitive drug antagonism. British Journal of Pharmacology and Chemotherapy, 4, 277-280.
85. 2-adrenoreceptor-mediated signaling. J. Biol. Chem., 273, 5109-5116.
86. SHEA, L.D., OMANN, G.M. & LINDERMAN, J.J. (1997). Calculation of diffusion-limited kinetics for the reactions in collision coupling and receptor cross-linking. Biophys. J., 73, 2949-2959.
87. SHORTLE, D. (1992). Mutational studies of protein structures and their stabilities. Quarterly Reviews of Biophysics, 25, 205-250.
88. SINE, S.M., CLAUDIO, T. & SIGWORTH, F.J. (1990). Activation of Torpedo acetylcholine receptors expressed in mouse fibroblasts: single channel current kinetics reveal distinct agonist binding affinities. Journal of General Physiology, 96, 395-437.
89. SINE, S.M., OHNO, K., BOUZAT, C., AUERBACH, A., MILONE, M., PRUITT, J.N. & ENGEL, A.G. (1995). Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron, 15, 229-239.
90. SMITH, G.B. & OLSEN, R. W. (1994). Identification of a [3H]muscimol photoaffinity substrate in the bovine Γ-aminobutyric acid A receptor α subunit. Journal of Biological Chemistry, 269, 20380-20387.
91. STEPHENSON, R.P. (1956). A modification of receptor theory. Br. J. Pharmacol., 11, 379-393.
92. STERN, P., BÉHÉ, P., SCHOEPFER, R. & COLQUHOUN, D. (1992). Single channel properties of NMDA receptors expressed from cloned cDNAs: comparison with native receptors. Proceedings of the Royal Society London B, 250, 271-277.
93. SUCHER, N.J., AWOBULUYI, M.N., CHOI, Y.-B. & LIPTON, S.A. (1996). NMDA receptors: from genes to channels. Trends in Pharmacological Sciences, 17, 348-355.
94. SWANSON, G.T., KAMBOJ, S.K. & CULL-CANDY, S.G. (1997). Single-channel properties of recombinant AMPA receptors depends on RNA editing, splice variation, and subunit composition. Journal of Neuroscience, 17, 58-69.
95. TOMASELLI, G.F., MCLAUGHLIN, J.T., JURMAN, M. E., HAWROT, E. & YELLEN, G. (1991). Mutations affecting agonist sensitivity of the nicotinic acetylcholine receptor. Biophys. J., 60, 721-727.
96. TUCEK, S. (1997). Is the R and R* dichotomy real? Trends in Pharmacological Sciences, 18, 414-416.
97. UNWIN, N. (1995). Acetylcholine receptor channel imaged in the open state. Nature, 373, 37-43.
98. VENTER, D.P. (1997). Efficacy I: a new method for estimating relative efficacy of full agonists via newly defined efficacy related parameter. Eur. J. Pharmacol., 320, 223-231.
99. VINCENT, A., NEWLAND, C., CROXEN, R. & BEESON, D. (1997). Genes at the junction - candidates for congenital myasthenic syndromes. Trends in Neurosciences, 20, 15-22.
100. WANG, H.-L., AUERBACH, A., BREN, N., OHNO, K., ENGEL, A. G. & SINE, S.M. (1997). Mutation in the M1 domain of the acetylcholine receptor α subunit decreases the rate of agonist dissociation. Journal of General Physiology, 109, 757-766.
101. WEISS, J.M., MORGAN, P.H., LUTZ, M.W. & KENAKIN, T.P. (1996a). The cubic ternary complex receptor-occupancy Model I. Model description. Journal of Theoretical Biology, 178, 151-167.
102. WEISS, J.M., MORGAN, P.H., LUTZ, M.W. & KENAKIN, T.P. (1996b). The cubic ternary complex receptor-occupancy model II understanding apparent affinity. Journal of Theoretical Biology, 178, 169-182.
103. WEISS, J.M., MORGAN, P.H., LUTZ, M.W. & KENAKIN, T.P. (1996c). The cubic ternary complex receptor-occupancy model. III. Resurrecting efficacy. Journal of Theoretical Biology, 181, 381-397.
104. i1α fusion protein. FEBS Letters, 419, 141-146.
105. i1α by expressing the proteins from chimeric open reading frames. Journal of Biological Chemistry, 272, 24673-24678.
106. WOOD, M.W., VANDONGEN, M.A. & VANDONGEN, M.J. (1997). An alanine residue in the M3-M4 linker lines the glycine binding pocket of the N-methyl-D-aspartate receptor. Journal of Biological Chemistry, 272, 3532-3537.
107. WYLLIE, D.J.A., BÉHÉ, P., NASSAR, M., SCHOEPFER, R. & COLQUHOUN, D. (1996). Single-channel currents from recombinant NMDA NR1a/NR2D receptors expressed in Xenopus oocytes. Proceedings of the Royal Society London, B 263, 1079-1086.
108. WYLLIE, D.J.A., BÉHÉ, P. & COLQUHOUN, D. (1998). Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. Journal of Physiology (London), 510, 1-18 (Erratum: J Physiol. (Lond). 1998, 512, 955).
109. WYLLIE, D.J.A., EDMONDS, B. & COLQUHOUN, D. (1997). Single activations of recombinant NMDA NR1a/NR2A receptors recorded in one-channel patches. Journal of Physiology (London), 501.P, 13P.
110. WYMAN, J. & GILL, S.J. (1990). Binding and Linkage Functional chemistry of biological macromolecules, University Science Books, Mill Valley, CA.
111. WYMAN, J., J & ALLEN, D.W. (1951). The problem of the heme Interactions in hemoglobin and the basis of the Bohr effect. Journal of Polymer Science, VII, 499-518