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Affinity Data VIVIAN CODY Medical Foundation of Buffalo, Inc., Buffalo, NY 14203

Thyroid hormones (Figure 1) are iodinated amino acids which are synthesized in the thyroid gland and travel through the gen eral circulation bound to serum proteins. While they have been shown to elicit a multitude of biological responses, the specific nature of their actions still remains unclear. However, as early as 1959 Jorgensen and his co-workers (1) had proposed that spec i f i c structural and stereochemical features of the thyroid hor mones were responsible for their hormone action. Because the thyroid hormones are transported through the bloodstream bound to the serum proteins thyroxine-binding globulin (TBG), thyrox ine-binding prealbumin (TBPA) and serum albumin (SA), and are bound to nuclear proteins which proportedly initiate hormone action (2), the question of conformational preferences becomes increasingly important. These special stereochemical properties arise from the steric influence of the diortho iodines upon the diphenyl ether conformation. Minimal steric interaction between the 3,5-iodines and the 2',6'-hydrogens is maintained when one ring is coplanar with, and the other perpendicular to, the plane of the two C-O ether bonds. This gives rise to two skewed conformations (Figure 2) which can be described by the torsion angles Φ(C5-C4-041-C1') and Φ' (C4-041-C1'-C6') of 0°/90° and 90°/0° for Φ/Φ', respec tively. Only the skewed conformer Φ/Φ' = 90°/0° has been ob served structurally, although the other has been implicated as an active conformer (3). This skewed conformation also imparts further stereospecific characteristics to the hormone Τ which contains only a single outer ring iodine. Because of the restricted rotation about the two diphenyl ether bonds, the chemically equivalent 3' and 5'iodines are conformationally distinct, giving rise to a distal (away) or proximal (near) conformation (Figure 3). To verify the importance of this conformational feature, numerous structural analogues of triiodothyronine were synthesized (4) in an effort to determine the biologically active conformer of T . 3

3

0-8412-0521-3/79/47-112-281$05.00/0 © 1979 American Chemical Society

Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

COMPUTER-ASSISTED DRUG DESIGN

282

3,5 3',5'-TETRAIODO-L-THYRONINE (T ) ;

4

Figure 1.

3,5, 3'-TRIIODO-L-THYRONINE (T ) 3

Principal thyroid hormones thyroxine (T ) and triiodothyronine showing their molecular conformation and numbering scheme

ΑΝΤΙ - SKEWED ( φ / φ ' = 0 ° / 9 0 ° )

h

(T ) s

SKEWED ( φ / φ ' = 90° | 0°)

Figure 2. Two examples of the skewed (φ/φ' = 90°/0°) (right) and antiskewed (φ/φ' = 0°/90°) (left) diphenyl ether conformation of thyroxine. In each case the molecule is viewed perpendicular and parallel to the inner ring plane.


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Thyroid Hormones-Receptor Interactions

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Distal/Proximal 3'-Substituents The conformational requirements for a c t i v i t y and protein binding were investigated with 2',3'-dimethyl-3,5-diiodοthyro nine as the model for a d i s t a l conformer of T3 and 2',5'd ime t hy 1-3,5-diio do thyronine as the proximal model ÇL,5,6) . These studies showed that the d i s t a l analogue i s hormonally active, having 50% as much goiter-suppressing a c t i v i t y as T4 and 13% as much calorigenic effect as Τ3 (_5) . The proximal analogue shows only 1-2% as much activity as the d i s t a l analogue i n these tests. Similar results were obtained i n experiments using pure TBG or whole serum (_7) , indicating that the requirements for serum protein binding are the same as that required for hormone activity. The f i r s t nuclear magnetic resonance (NMR) studies of Τ3 f a i l e d to isolate two distinct spectra for the d i s t a l and proxi mal conformers (jB) . In addition, molecular orbital (MO) calcu lations predicted a high barrier to internal rotation about the diphenyl ether bonds (9). These data suggested that there was only one conformer present i n solution, presumably d i s t a l , since this was shown to be the active form of the hormone. However, the f i r s t crystal structure of T3 showed the 3'-I conformation to be proximal (10), inconsistent with available binding and a c t i v i t y data. This apparent dilema was resolved when further crystallographic data on Τ3 compounds became available (11,12,13,14,15). (See reference 11 for a detailed l i s t of thyroactive crystal structure studies.) These determinations show the 3'-I i n the d i s t a l conformation and further showed that either the d i s t a l or proximal conformer could be isolated by changing the crys t a l l i z i n g media (13,14). These data prompted further NMR and MO studies which showed a nearly equal distal/proximal ratio in solution (16) and a much smaller barrier to internal rotation (17). Thus these data have shown that the d i s t a l and proximal conformers are readily accessible i n solution and that the energy barrier to free rotation i s small enough so that the stereospecific conformer required by a receptor i s easily accessible. Cisoid/Transoid Conformation In addition to the conformational asymmetry of the outer phenyl ring, the thyronine nucleus possesses other conformational f l e x i b i l i t y (Figure 4). The preferred relative orientation (18) of the inner phenyl ring with respect to the amino acid (χ #90°) is such that the alanine side chain and the outer phenyl ring l i e either on the same side of the inner phenyl ring plane (eisoid) or on opposite sides of the inner ring plane (transoid) as shown i n Figure 5. Although the biological relevance of these conformers i s not known, they are observed with equal frequency. 2



284

Figure 4.

Thyroxine with amino acid conformational parameters defined


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Figure 5.

285

Thyroid hormones illustrating transoid and eisoid overall conformation



286 Diphenyl Ether Conformation

As mentioned, the torsion angles φ and φ' describe the relative orientations of the two phenyl rings with respect to the C-O-C ether plane. While the bulky 3,5-iodines maintain a perpendicular ring arrangement (6), (the ideal skewed conforma tion i s φ/φ' = 90°/0°) analysis of these data suggest further correlations i n the parameters which influence the diphenyl ether conformation. The plot of φ versus φ (Figure 6) shows two lines corresponding to the eisoid and transoid conformers. The graph also shows that the data are grouped into two clusters, one near the skewed conformer (φ/φ = 90°/0°) and another, twistskewed, near φ = 108°, φ' = -28° or φ = -108°, φ' = 2 8 ° . Further inspection of those structures involved shows that the deamino acids (thyroformic, acetic, propionic) tend to be skewed (19) whereas the iodοthyronines are twist-skewed. These observations suggest that the α-amino nitrogen i s responsible for the long range transmission of conformational effects. The significant differences between these conformers are reflected i n the disposition of the 4 -0H (Figure 7a) when the inner ring i s used as the common structural feature or i n the displacement of the inner phenyl ring and side chain (Figure 7b) when the outer ring i s used as the common feature. Depending on the receptor-site binding requirements, these differences may be directly linked to variations in receptor binding a f f i n i t y and hormone activity. 1

1

f

Hydrogen Bonding An analysis of the hydrogen bonding and molecular packing of the thyroactive compounds i n their crystal l a t t i c e offers an insight into the molecular details of hydrogen bond strength and directionality at the hormone-receptor s i t e . In the thyronine nucleus (1) the amine acts as a hydrogen bond donor, (2) the carboxylic acid group acts as a hydrogen bond acceptor, and (3) the 4 -0H can act both as a hydrogen bond donor and acceptor, depending on i t s environment. A study of the hydrogen bonding observed i n these crystal structures (11) shows that there i s a high degree of directional s p e c i f i c i t y i n the location of hydro gen bond donors and acceptors. In those structures where the 4 -OH acts as a hydrogen bond donor (Table I, Figures 8 and 9), the acceptor atom i s a carbox y l i c oxygen from an adjacent molecule i n the l a t t i c e . The acceptor atoms approach the 4'-OH from directions nearly coplanar with the phenoxy ring plane (C3 -C4 -04 1...X) and at an angle (C4 -04 1...X) of 120°. In addition, for T structures, the direction of approach i s trans to the 3 -iodine, whether d i s t a l or proximal. When the 4'-OH acts as a hydrogen bond acceptor, the donor atoms (Table I) tend to approach the phenoxy ring from directions either above or below the plane and opposing the f

f

,

f

,

t

,

3

1


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Figure 7. Superposition of a skewed (dark) diphenyl ether conformation on a twist-skewed (light) conformation, (a) Overlap of inner ring as common structural feature and (h) the outer phenyl ring.



2.59 2.82

119 118

162 -177

08 010

f

2

acid

2

3 -isopropyl-diiodothyronine H 0 (25)

1

2 ,3 -dimethyl-diiodothyronine H 0 (24)

1

triiodothyropropionic ethyl ester (23)

triiodothyronine, HC£, H 0 (22)

09

160

115

2.75

2.63

124

151

09

triiodothyronine (13)

2

2.59

119

-176

09

triiodothyroacetic acid (19)

triiodothyronine methyl ester (14)

diiodothyropropionic acid (21)

acid (11)

dibromothyroacetic

2.972 2.04 124° 116

38° -77

N4 N8

2.62&

108°

-175°

09

0...X

f

X

,

0...X

01 01

-83 -6

127 127

2.51 2.73

3.17 2.51

2.68 2.69 127 119 108 176 02 03

113 137

2.82 151 -10 N8

-94 49

3.02 145 33 07

01 02

2.69 126 168

N8

f

C4 -04 l ...X

f

f

4 -OH as Acceptor C3 -C4 04'1...X

diiodothyronine (20)

,

X

Structure

I

C4 -04 1 .. .X

f

!

f

C3 -C4 04 1...X

f

4 -0H as Donor

Hydrogen Bond Directionality i n Thyroactive Structures

Table I


2.71 2.70 2.65 2.60 2.65 2.70

132 118 113 134 113 130

89 -78 73 -102 73 109

N4* N4**

thyroxine (11)

N8 N44 N8* N43

A

Β

tetraiodothyroformic acid

(υ)

2.59

3.08

108

150

118

178

09

04Ί 07*

tetraiodothyroacetic acid (19)

C3'-C4'04Ί...Χ

X

2.91

0...X 145

C4'-04'l ...X -25

thyroxine, HC£, H 0 (22)

2

C3'-C4'04Ί...Χ

0. ..:

Χ

4'-OH as acceptor C4'-04'l .. .X

Structure

4 -0H as Donor

f

Table I. (Continued)

Figure 8. Example of the direction of approach of (a) hydrogen bond acceptor to the 4'-OH of T ; (b) hydrogen bond donor and acceptor to the 4''-hydroxyl of T ; and (c) hydrogen bond donors to the 4'-phenoxide of Τ\ 3

3


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291


292

acceptor atom (Figure 8b). As seen from Table I, the average value for the hydrogen bond angle C4-04 1...X i s 116° when the 4 -0H acts as a donor and 129° when i t i s an acceptor. Also, when the 4 -0H i s simulta neously involved as a donor and acceptor, the donor atom to 4 -0H tends to have an angle near 150°. In those situations where the hydrogen bonding atoms are water, one adopts the orientation observed for the carboxylic oxygens, suggesting that i t i s a hydrogen bond acceptor from the 4 -0H. In the case of tetraiodothyroactive structures where the 4'-oxygen i s a phenoxide ion (11) and thus only a hydrogen bond acceptor, the donor atoms approach the 4*-phenoxy ring symmetri cally from directions both above and below the plane (Figure 8c). However, where the tetraiodo structures are hydroxyIs (T^A (19)), the outer ring iodines cause the approach of the donor/acceptor atoms to deviate from this pattern. A study of the 4 -0...X hydrogen bonds i n these structures shows that the average 0...0 distance i s 2.74$ and the 0...N distance i s in general agreement with other studies (26). When the donor and acceptor 0...0 values are considered sepa rately, these become 2.668 and 2.8l8 for 4 -0H as a donor and acceptor, respectively. The results of theoretical energy calculations of interand intramolecular hydrogen bond strengths of ortho substituted phenols and phenoxides (27), as models to investigate l i k e l y orientations of thyroid hormones at their protein binding sites, are i n general agreement with the hydrogen bonding patterns observed in these crystallographic determinations. These energy calculations predict an average 0...0 distance of 2. 63X and a C-0...0 angle of 125°, irrespective of whether the 4 -0H i s acting as a proton donor or acceptor. Unfortunately, this study (27) did not compute the hydrogen bond geometry when the 4 -0H is simultaneously acting as a hydrogen bond donor and acceptor and consequently the detail observed from the crystallographic data i s not apparent. The observation that i n the 3 -substituted structures the hydrogen bonding atom approaches the 4 -0H trans to the 3'-sub stituent i s verification of quantitative structure activity relationship (QSAR) data which also suggest that in vitro binding of Τ3 probably involves hydrogen bond donation of the 4 -0H to the 5'-side of the nuclear receptor (28). ?

f

f

?

f

f

f

f

f

1

f

f

Protein Binding Characteristics Because thyroid hormones are protein boun^i throughout the general circulation as well as i n the c e l l membranes and nucleus, protein binding is central to the transport, tissue distribution and metabolism rates of the various thyroid analogues (29). Current theory proposes that the hormone f i r s t binds at a spe c i f i c site on the protein receptor and then an interaction


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293

between the hormone and a complementary receptor component takes place. Steric correspondence between the receptor site and the hormone then permits electronic interaction. Thus, the struc tural s p e c i f i c i t y of the hormones can be both steric and elec tronic i n nature. The importance of specific structural features in binding to the various thyroid binding proteins has been suggested from numerous studies measuring the relative binding a f f i n i t i e s of the hormones and their analogues for these serum, nuclear and membrane proteins (30-36). These studies indicate that the binding site requirements are different for each of the proteins. Table II l i s t s a few of the activity and binding a f f i n i t y data available for the thyroid hormones and their analogues to membrane, serum and nuclear proteins (11). Structural require ments for potency correlate closely with those for in vitro binding to nuclear proteins (37). These correlations, i n con junction with other thyroid hormone studies, provide a general description of the structural features required for binding and hormonal activity (Table I I I ) . As illustrated, the major binding requirements d i f f e r principally with regard to the 3 ,4 ,5'-sub stituents. The nuclear receptors preferentially bind to d i s t a l l y 3'-oriented compounds, as do the membrane bound proteins, while the serum proteins have maximal binding for 3 ,5'-disubstituted compounds with electron withdrawing groups. Also, from pH depen dency studies of T and T binding, i t i s apparent that 4 -0H binds to the nuclear receptors i n i t s un-ionized form whereas i t binds to the serum protein receptors i n i t s ionized form (28,30). These results correlate well with the crystallographic observa tions of structures as 4'-phenoxide ions and T as un-ionized 4'-hydroxyls. f

f

1

f

3

4

3

Receptor Models Recent crystallographic studies of thyroxine-binding pre albumin (38,39,40) show i t to be a tetramer with a channel running through the structure. The four units are related by two perpendicular 2-fold axes. Complexes of TBPA with Ti+ and Τ3 show the hormones are bound inside the channel (Figure 10) with the 4'-phenoxy ring pointed toward the center of the core. However, because the thyroid hormones cannot be accommodated by the symmetry requirements of the protein, their exact orientation in the receptor s i t e cannot be defined. Instead, an average position of two symmetry related orientations i s observed. Nevertheless, this description of TBPA structural features, com bined with relative binding a f f i n i t y data (41) of analogues to TBPA, permits a detailed model of the hormoiie-receptor inter action to be formulated. In this case, the 4'-phenoxy ring i s tightly bound, v i a hydrogen bonds, to a water or peptide func tional group (39) suggesting that 4'-0H interactions are a primary requirement for binding. I f , on the other hand, the side



!

3

3

3

4

1

f

1

1

L-thyroxine (Ti+) D-thyroxine tetraiodothyropropionic acid (T P) tetraiodothyroacetic acid (Ti+A) tetraiodothyroformic acid (Ti+F) te trabromo-DL-thyr onine tetramethy1thyronine 2 ,3 -dimethyl-3,5-diiodo thyronine 2',5 -dimethy1-3,5-diiodothyronine 3,5,3'-triiodo-L-thyronine (T ) 3 ,5 ,3-triiodothyronine (RT ) triiodothyroacetic aeid (T A) tr ime thy1thyronine

Compound 39.3% .95 76.4 100.0 90,2

1.4 3.1 4.7

-

100.0% 54.0 3.6 1.7 40.0 0.0 0.71 0.13 9.0 38.0 0.3

-

-

TBPA (41)

TBG (33)

0.1

-

1.1 0.1 100.0 0.1

—

67.5 60.6

100.0

-

0.3 6.3 0.1 100.0 best binder

1

f

3

Membrane

appears to be similar to the nuclear proteins

A l l proteins require a diiododiphenyl ether nucleus. The implications of these data are that TBG and nuclear proteins prefer a twist-skewed diphenyl ether conformation whereas TBPA prefers a skewed diphenyl ether.

chain orientation and composition were of primary importance, as suggested from TBG and nuclear protein data (30,31,32,33), then the consequences of changes i n the side chain orientation (χ , χ , Figure 4) would be significant. The most striking feature of the data l i s t e d i n Table II i s that the acid metabolites bind more strongly to TBPA than thyrox ine; just the opposite of the order observed for TBG and the nuclear proteins. A factor which may influence these parameters is the relative importance to binding of the diphenyl ether con formation and the side chain conformation. As was shown (19), the thyroactive acid structures prefer a skewed diphenyl confor mation whereas the thyronine structures adopt a twist-skewed con formation. As illustrated (Figure 7), there i s significant dis placement of the 4'-OH and side chain functional groups between these two conformers. Therefore, i f 4'-phenoxy interactions control binding, these differences w i l l affect the position of the side chain groups within the binding channel. When the molecular structures of the acid metabolites T A (dark, Figure 11) i s successively superimposed over that of (a) Ti+F, (b) Ti+P, (c) T , and (d) a l l of them; i t can be seen that the acid side chains describe a probably binding volume from which the T4. amine i s excluded. In addition, the Ti+ inner ring has the largest deviation from the positional range described by the acid metabolites. Also, the carboxylic oxygens of the various metabolites (except T 4 F ) , irrespective of composition, 1

2

4

4


Figure 11. Superposition of molecular structure of T A with (a) T F; (b) T^P; (c) T\; and (d) all of them, illustrating binding volume of thyroactive acid metabolites, assuming 4'-phenoxy ring fixed. h

If


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Thyroid

Hormones—Receptor

Interactions

297

tend to cluster together, suggesting that this feature may also be of importance i n determining relative binding a f f i n i t y . Analysis of the TBPA-T^ complex (39,40) indicates that the binding site for the hormone i s located deep inside the channel. The hormone makes extensive interactions with the protein side chains that project into the channel. The 4'-hydroxy1 of T^ interacts with a patch of hydroxy-amino acids of the protein while each of the iodines makes contact with a number of hydro phobic protein residues. The Ti+ amino acid side chain functional groups are i n appropriate positions to interact with glutamic acid and lysine residues. Thus, this channel provides a favorable environment for each of the characteristic substituents of the thyroid hormone (40) . However, because of the Ti+ orientation disorder i n the protein complex, this structural model i s not a sensitive measure of the observed correlations between diphenyl ether conformations and binding a f f i n i t y data. The differences i n binding orders between TBPA and TBG suggest that different structural features may play a key role in receptor interactions. I t has been shown (4,28) that TBG also preferentially binds to a tetraiodo-4 -phenoxide ion, but since Τΐψ i s the strongest binder, this suggests a different side chain stereochemistry. Here we can assume that i t i s the twist-skewed diphenyl ether conformation which orients the Ti+ side chain for optimal receptor-hormone interactions. In the case of the nuclear proteins optimal binding i s observed for a d i s t a l l y oriented 3 -I and a 4 -hydroxyl. Side chain requirements appear to be similar to those of TBG (28,31). Therefore, changes i n the relative binding a f f i n i t i e s of thyroid hormone structures to receptors w i l l ultimately depend upon the specific steric requirements of the binding site and the a b i l i t y of the hormones to adopt the required conformation. In addition, the net charge of the hormone could also influence i t s binding a b i l i t y . Thus, the observation of conformational patterns among thyroactive structures which correlate with function, activity and binding data provide useful information in describing specific types of hormone-receptor interactions. T

!

f

Acknowledgements This research was supported i n part by a grant from HEW AM-15051. Graphs and figures were prepared through interro gation of the thyroid data stored i n the NIH PROPHET system, an NIH interactive computer network. The secretarial and technical assistance of Mrs. B. Giacchi, Miss M. Tugac, Miss G. Del Bel and Mrs. C. DeVine are gratefully acknowledged.

Literature Cited 1.

Zenker, N.; Jorgensen, E. C. J . Amer. Chem. Soc., 1959, 4643.


81,

298 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.


Oppenheimer, J . H . ; Schwartz, H. L.; Surks, M. I.; Koerner, D.; Dillman, W. H. Recent Progr. Horm. Res., 1976, 32, 529. Lehmann, P. A. J. Med. Chem., 1972, 15, 404. Jorgensen, E. C. Pharmac. Ther., 1976, B2, 661. Jorgensen, E. C.; Lehmann, P. Α.; Greenberg, C.; Zenker, N. J . Biol. Chem., 1962, 237, 3832. Jorgensen, E. C. Mayo Clinic Proc., 1964, 39, 560. Schussler, G. C. Science, 1972, 178, 172. Lehmann, P. Α.; Jorgensen, E. C. Tetrahedron, 1965, 21, 363. Kier, L. B.; Hoyland, J. R. J. Med. Chem., 1970, 13, 1182. Camerman, N.; Camerman, A. Science, 1972, 175, 764. Cody, V. Recent Progr. Horm. Res., 1978, 34, 437. Cody, V. Science, 1973, 181, 757. Cody, V. J. Amer. Chem. Soc., 1974, 96, 6720. Cody, V. J . Med. Chem., 1975, 18, 126. Cody, V.; Duax, W.L. Biochem. Biophys. Res. Comm., 1973, 52, 430. Emmett, J . C.; Pepper, E. S. Nature, 1975, 257, 334. Kollman, P. Α.; Murray, W. J.; Nuss, M. E.; Jorgensen, E. C.; Rothenberg, S. J . Amer. Chem. Soc., 1973, 95, 8518. Cody, V.; Duax, W. L.; Hauptman, H. A. Int. J . Peptide Protein Res., 1973, 5, 297. Cody, V.; Hazel, J . P.; Langs, D. Α.; Duax, W. L. J. Med. Chem., 1977, 20, 1628. Cody, V.; Duax, W. L.; Norton, D. A. Acta Cryst., 1972, B28, 2244. Cody, V.; Erman, M.; DeJarnette, F. E. J. Chem. Res., 1977, S, 126. Camerman, Α.; Camerman, N. Acta Cryst., 1974, B30, 1832. Camerman, N.; Camerman, A. Can. J. Chem., 1974, 52, 3048. Fawcett, J . K.; Camerman, N.; Camerman, A. Can. J. Chem., 54, 1317. Fawcett, J . K.; Camerman, N.; Camerman, A. J . Amer. Chem. Soc., 1976, 98, 587. Mitra, J.; Ramakrishnan, C. Int. J . Peptide Protein Res., 1977, 9, 27. Andrea, Τ. Α.; Dietrich, S. W.; Murray, W. J.; Kollman, P. Α.; Jorgensen, E. C.; Rothenberg, S. J . Med. Chem., 1979, 22, 221. Dietrich, S. W.; Bolger, M. B.; Kollman, P. Α.; Jorgensen, E. C. J . Med. Chem., 1977, 20, 863. Pittman, C. S.; Pittman, J . A. In:"Physiology, Vol. III, Thyroid", Greer, Μ. Α.; Solomon, D. H . , Ed.; American Physiological Society: Washington, D.C., 1974. Tabachnick, M.; Korcek, L. Biochimica et Biophysica Acta, 1978, 537, 169. Koerner, D.; Schwartz, H. L.; Surks, M. I.; Oppenheimer, J . H.; Jorgensen, E. C. J. Biol. Chem., 1975, 250, 6417. Goldfine, I. D.; Smith, G. J.; Simons, C. G.; Ingbar, S. H.; Jorgensen, E. C. J. Biol. Chem., 1976, 251, 4233.


13. 33. 34. 35. 36. 37. 38. 39. 40. 41.

Cody


299

Snyder, C. M.; Cavalieri, R. R.; Goldfine, I. D.; Ingbar, S. H.; Jorgensen, E. C. J. Biol. Chem., 1976, 251, 6489. Spindler, B. J.; MacLeod, Κ. M.; Ring, J.; Baxter, J . D. J . Biol. Chem., 1975, 250, 4113. Singh, S. P.; Carter, A. C.; Kydd, D. M.; Costanzo, R. R. Endocrine Res. Comm., 1976, 3, 119. Sterling, K.; Milch, P. O.; Brenner, Μ. Α.; Lazarus, J. H. Science, 1977, 197, 996. Jorgensen, E. C. In: "The Thyroid", Werner, S. C.; Ingbar, S. H., Ed.; Harker & Row, 1978; p. 125. Blake, C. C. F.; Geisow, M. J.; Swan, I. D. Α.; Rerat, C.; Rerat, B. J . Mol. Biol., 1974, 88, 1. Blake, C. C. F . ; Oatley, S. J . Nature, 1977, 268, 115. Blake, C. C. F. Endeavour, 1978, 2, 137. Andrea, T. A. Ph.D. Thesis, 1977, University of California, San Francisco.

Received June 8, 1979.


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