Efficacy of Demineralized Bone Matrix for Revision Alveolar Bone Grafting in Patients Previously Treated with Bone Morphogenetic Protein 2 (BMP-2).

OBJECTIVE: This study investigates the effectiveness of demineralized bone matrix (DBX) to close alveolar clefts in patients previously treated with bone morphogenic protein-2 (BMP-2) who remained with bone nonunion. DESIGN: This is an IRB-approved retrospective, single-center study. SETTING: This study was conducted at a tertiary academic center. PATIENTS/PARTICIPANTS: We searched for all surgical encounters with the Current Procedural Terminology (CPT) code 42210 from the years 2013-2019. Included patients were diagnosed with cleft alveolus, previous BMP-2 exposure and required revision bone grafting during mixed dentition for persistent alveolar defects. INTERVENTIONS: 17 patients underwent revision alveolar bone grafting (ABG) with either DBX (n = 10) or autograft (n = 7) to repair persistent bony cleft. MAIN OUTCOME MEASURE(S): The primary study outcome measured was alveolar bone graft revision failure described as continued alveolar nonunion. RESULTS: The median age at revision ABG was 13.1 ± 3.3 years, with a mean follow-up time of 4.9 years (1.1-9.2 years). Patients were 53% male, 47% had a unilateral cleft lip and alveolus. 58.8% of patients were treated with DBX in the cleft, 41.2% treated with autograft from iliac crest. Overall, 11.8% (n = 2) of all revisions failed, requiring a second revision. The average time to reoperation was 2.06 years, and both were re-grafted with autograft. There was no statistically significant difference between the type of bone graft source used and the failure rate obtained (P = .1544). CONCLUSIONS: DBX and autologous iliac crest bone grafts achieve similar alveolar union rates during revision ABG in patients treated with previous BMP-2 to the alveolar cleft.

Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii.

Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased Km values for dihydrofolic acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino acid substitutions (S106P and E127G) showed a doubling of kcat, as well as a Km for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.

A phenomenological model for the photocurrent transient relaxation observed in ZnO-based photodetector devices.

We present a phenomenological model for the photocurrent transient relaxation observed in ZnO-based metal-semiconductor-metal (MSM) planar photodetector devices based on time-resolved surface band bending. Surface band bending decreases during illumination, due to migration of photogenerated holes to the surface. Immediately after turning off illumination, conduction-band electrons must overcome a relatively low energy barrier to recombine with photogenerated holes at the surface; however, with increasing time, the adsorption of oxygen at the surface or electron trapping in the depletion region increases band bending, resulting in an increased bulk/surface energy barrier that slows the transport of photogenerated electrons. We present a complex rate equation based on thermionic transition of charge carriers to and from the surface and numerically fit this model to transient photocurrent measurements of several MSM planar ZnO photodetectors at variable temperature. Fitting parameters are found to be consistent with measured values in the literature. An understanding of the mechanism for persistent photoconductivity could lead to mitigation in future device applications.

Practice Trends in the Management of Asymptomatic Breast Reconstruction Patients with Textured Implants: A Survey Analysis.

Despite the increasing prevalence of breast implant associated anaplastic large cell lymphoma, there remains a paucity of literature guiding management of asymptomatic patients with textured breast implants. This risk can be anxiety provoking in breast reconstruction patients given their history of cancer or increased future risk. The purpose of this study is to evaluate current practice trends when managing the concerned asymptomatic patient following textured implant-based breast reconstruction. Methods: An electronic survey was distributed to members of the American Society of Plastic Surgeons, regarding management of asymptomatic breast reconstruction patients with textured devices. Anonymous responses were collected, and statistical analysis was performed. Results: A total of 304 responses were received. Of respondents, 237 (92%) have managed asymptomatic patients with textured devices. Historically, the overwhelming majority (89%) used textured devices; however, only 25% report current use. Regarding management of asymptomatic breast reconstruction patients, 87% recommend conservative management, while 13% recommend surgical management. When surgery is performed, 16.3% of respondents elected for implant exchange, 33.8% recommended implant exchange with partial capsulectomy, and 49.8% elected for implant exchange with total capsulectomy. Evaluation of practice patterns based on demographics demonstrated statistically significant differences in current use of textured devices and management of acellular dermal matrix. Conclusions: Despite decreased current use, there is a significant population of asymptomatic breast reconstruction patients with a history of textured devices concerned for risk of breast implant associated anaplastic large cell lymphoma. This survey demonstrates ongoing variability in surgeon recommendations regarding conservative and surgical management of these patients and the need for continued development of evidence-based guidelines.

Radioactive and stable isotopes reveal variations in nearshore submarine groundwater discharge composition and magnitude across low inflow northwestern Gulf of Mexico estuaries.

To determine how submarine groundwater discharge (SGD) magnitudes and composition (fresh or saline/recirculated) vary in nearshore low inflow estuaries across ⁓125 km of a semiarid coastline, this study assessed three south Texas estuaries, using radon [222Rn], radium [226Ra and 224Ra], and water isotopes [δ18O and δD]. Mass balance models of time-series 222Rn, found to be representative of total SGD in this study, revealed much higher SGD inputs to the Nueces Estuary (average [x̅] Nueces, Corpus Christi and Oso Bays: 120, 83, and 44 cm·d-1, respectively), attributed to anthropogenically-disturbed substrates and potentially surfacing growth-faults. The lowest 222Rn-derived SGD occurred in the Upper Laguna Madre Estuary (x̅: Upper Laguna Madre and Baffin Bay: 21 and 18 cm·d-1, respectively), explained by the drier climate, lower anthropogenic disturbance, and neighboring groundwater cone of depression. Aransas Bay in the Mission Aransas Estuary received greater average annual precipitation but exhibited low total SGD rates (x̅: 23 cm·d-1). Seasonally, average 222Rn-derived SGD rates increased following Hurricane Harvey (43 cm·d-1 in spring to 64 cm·d-1 in summer). In the Nueces Estuary, the overall 222Rn-derived SGDs were substantially higher than SGDs from 224Ra and 226Ra. The closer agreement between 224Ra and 222Rn-derived SGD and larger 224Ra rates in the Upper Laguna Madre Estuary, Aransas Bay and Oso Bay indicate that saline/recirculated SGD contributions were significant. Values of δ18O and δD confirm these types of inputs, with effects of evaporation/salinization more pronounced where recirculation was predominant and the opposite where terrestrial/222Rn-derived SGD inputs dominate. 226Ra-derived SGDs were lower than the 224Ra due to different behavior of the two isotopes while released into water following transport through saline and fine-grained estuarine sediments or due to wind-driven disturbances.

Parental Rejecting Behaviors: Validating a Behaviorally Based Youth-Report Measure of Parental Emotional Abuse.

Positive and warm parental attitudes are associated with better social and emotional child functioning, whereas negative or rejecting parental attitudes are associated with poor outcomes, such as aggression, impaired self-esteem, and emotional instability. The current study investigated the reliability and validity of scores on an interview adaptation of a measure of parental rejecting behavior (PRB) in a sample of detained adolescents. Participants (N = 198) completed a measure assessing their memories of the frequency of specific parental behaviors associated with rejection and self-report measures of exposure to abuse/neglect and community violence, and internalizing and externalizing psychopathology. PRB scores were internally consistent and associated with several kinds of child maltreatment. PRB scores correlated uniquely with indices of internalizing and externalizing symptomatology, even after controlling for indices of overall child maltreatment or a specific index of emotional abuse. The pattern of correlations suggests that the measure provides a valid index of parental emotional abuse, which may help identify youth at risk for both internalizing and externalizing disorders.

Molecular conformation of a halogen-free thyroxine analog: 4-Methoxy-3,5,3-trimethyl-L-thyronine N-acetyl ethyl ester.

The molecular conformation of the halogen-free thyroxine analog 4-methoxy-3,5,3'-trimethyl-L-thyronine -n-acetyl ethyl ester has been determined by x-ray diffraction techniques. The unsubstituted parent compound, trimethylthyronine, has significant biological activity in rat thymocyte tests when compared with the thyroid hormone 3,5,3'-triiodo-L-thyronine (T3). Although no activity data are available for the analog studied, it is presumed to be inactive because of the 4-methoxy blocking group. The observed conformation of this structure is similar to that found for the natural hormone T(3). The 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist-skewed. The results of this diffraction study show that methyl substituents are capable of maintaining the thyronine conformation required for hormonal activity; they suggest that iodine enhances hormone-protein binding because of the electronic effects it produces either by alteration of molecular charge distributions or by direct charge-transfer interactions with the serum or nuclear binding proteins.

Distal conformation of the thyroid hormone 3,5,3'-triiodo-L-thyronine.

In the crystal structure of the thyroid hormone, 3,5,3'-triiodo-L-thyronine, the 3' iodine is observed in the distal position, away from the alaninebearing ring of the thyroid hormone. This result had been anticipated from stereochemical and biological activity studies. However, previous observations of structures in which the 3' iodine was proximal had cast some doubt on the stability of the 3' distal conformation. This observation suggests that the relative energies of the two conformers is similar and that perhaps the barrier to rotation is not as great as previously supposed since both the distal and proximal conformers have now been observed in the solid state.

Rabbit skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase activity: stimulation in vitro by thyroid hormone analogues and bipyridines.

Sarcoplasmic reticulum-enriched membranes from rabbit skeletal muscle contained Ca(2+)-ATPase activity which was significantly enhanced (26% increase, P < 0.001) in vitro by physiological concentrations (10(-10) M) of L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3). In contrast, the biologically inactive iodothyronine analogues D-T4 and 3,3',5,5'-tetraiodothyroacetic acid (Tetrac) (10(-10) M) were without effect on enzyme activity. 3,5-Dimethyl-3'-isopropyl-L-thyronine (Dimit), a bioactive analogue, was highly effective as a Ca(2+)-ATPase stimulator, increasing enzyme activity by 43% (P < 0.02 vs. T4 effect). A bipyridine cardiac inotropic agent, milrinone, has been reported to be thyromimetic in a myocardial membrane Ca(2+)-ATPase system, and in concentrations from 10(-10) to 10(-5) M enhanced skeletal muscle SR membrane Ca(2+)-ATPase activity in vitro (P < 0.001). Milrinone analogues which have been previously shown to enhance rabbit myocardial membrane Ca(2+)-ATPase activity, and which have a twist relationship of the pyridine rings, were also striated muscle Ca(2+)-ATPase stimulators. We conclude that (1) striated muscle is a mammalian tissue in which physiological levels of biologically relevant thyroid hormone analogues, particularly Dimit, stimulate Ca(2+)-ATPase activity in vitro by a non-genomic mechanism; (2) cardiac bipyridine analogues which are thyromimetic in vitro in rabbit heart, and which have structural homologies with thyroid hormone, are stimulators of rabbit striated muscle sarcoplasmic reticulum Ca(2+)-ATPase activity.

Purification and crystallization of Lactobacillus casei folylpolyglutamate synthetase expressed in Escherichia coli.

Folylpolyglutamate synthetase (FPGS) from Lactobacillus casei has been crystallized with polyethylene glycol and acetate buffer at pH 5.0. The enzyme was obtained from Escherichia coli strain SF4 harboring the L. casei FPGS chromosomal gene on a pEMBL vector (pGT3-8.1). Crystals of the enzyme were obtained which diffract to 2.6 A resolution. The crystals are monoclinic, space group P2(1), with unit cell dimensions of a = 54.07 A, b = 45.83 A, c = 84.37 A and beta = 107.92 degrees. A unit cell contains one molecule of the 43,000 Da enzyme per asymmetric unit. A complete X-ray data set on the native crystals has been collected.

Computer-assisted molecular modeling of benzodiazepine and thyromimetic inhibitors of the HepG2 iodothyronine membrane transporter.

T3 cellular uptake is inhibited in the presence of benzodiazepines (BZs). The structure-activity relationship of BZ inhibition correlates strongly with halogen substitution of the nonfused phenyl ring and indicates that this ring is required for activity. A structure-activity series of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transporter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of the substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as HepG2 iodothyronine transport inhibitors, and therefore the potent inhibitors were restricted to the BZ and TH compounds. Using both of these BZ and TH structure-activity series along with computer-assisted molecular modeling techniques, we determined which chemical structural components were important at the transporter interaction site. By superimposing structures from active chemicals, excluding residues from poor inhibitors, and incorporating molecular electropotential data, we developed a five-point model of BZ conformational similarity to the endogenous transporter ligand, L-T3: the alkyl substitution at the N1 of the BZ ring seems to simulate the alanine side chain of T3, and the electro-negative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' of BZ form a pyramidal pharmacophore that seems to correspond with the 3-l/5-l/3'-l/4'-OH substituents of T3, respectively. These points, suggesting a tilted cross-bow formation, may be sites for ligand interaction with the iodothyronine transporter.

Microfabrication, separations, and detection by mass spectrometry on ultrathin-layer chromatography plates prepared via the low-pressure chemical vapor deposition of silicon nitride onto carbon nanotube templates.

Microfabrication of ultrathin-layer chromatography (UTLC) plates via conformal deposition of silicon nitride by low-pressure chemical vapor deposition onto patterned carbon nanotube (CNT) scaffolds was demonstrated. After removal of the CNTs and hydroxylation, the resulting UTLC phase showed no expansion or distortion of their microfeatures and the absence/reduction of remaining nitrogenic species. Developing time of a mixture of lipophilic dyes on this UTLC plates was 86% shorter than on high-performance thin-layer chromatography (HPTLC) plates. A water-soluble food dye mixture was also separated resulting in low band broadening and reduced developing time compared to HPTLC. For the latter example, mobile phase optimization on a single UTLC plate consisted of 14 developments with different mobile phases, each preceded by a plate prewashing step. The same plate was again reused for additional 11 separations under varying conditions resulting in a development procedure with a mean separation efficiency of 233,000theoretical plates/m and a reduced mobile phase consumption of only 400µL. This repeated use proved the physical robustness of the ultrathin layer and its resistance to damage. The layer was highly suited for hyphenation to ambient mass spectrometry, including desorption electrospray ionization (DESI) mass spectrometry imaging and direct analysis in real time (DART) mass spectrometry.

Threonine for alanine substitution at position 109 of transthyretin differentially alters human transthyretin's affinity for iodothyronines.

The heterozygous substitution of threonine for alanine at amino acid 109 of human transthyretin (TTR) increases its affinity for T4. We compared the affinity of recombinant wild-type (WT) and Thr109-TTRs for various iodothyronines in an attempt to elucidate how this mutation alters the T4-binding site. Homozygous WT and Thr109-TTRs were expressed recombinantly in Escherichia coli, and heterozygous Thr109-TTR was purified from plasma. The affinities of the iodothyronines for TTR were determined by measuring [125I]T4 bound by TTR in the presence of increasing concentrations of unlabeled iodothyronines. Homozygous Thr109-TTR bound T4 with an affinity slightly, but not significantly, greater than that of heterozygous Thr109-TTR. The affinity of Thr109-TTR for all iodothyronines was higher than that of WT TTR. However, the Thr109 mutation increased TTR's affinity for T4, Triac (triiodothyroacetic acid), and T3 to a greater extent than it did for Tetrac (tetraiodothyroacetic acid), EMD21388 (3',5'-dibromo-4',6'-dihydroxy-3-methylflavone), and dextro-T4. These data demonstrate that a subtle change in the structure of the T4-binding channel in TTR differentially alters the affinity of binding of various iodothyronines and suggests that site-directed mutagenesis of residues within the binding channel might clarify the relative importance of specific domains of this binding channel.

Role of iodine in thyroid hormones: molecular conformation of a halogen-free hormone analogue.

The molecular conformation of the halogen-free thyroid hormone analogue, N-acetyl-4'-methoxy-3,5,3'-trimethyl-L-thyronine ethyl ester, has beeen determined by X-ray diffraction techniques. The observed molecular conformation is similar to that found for the natural hormone 3,5,3'-triiodo-L-thyronine (T3). In this structure, the 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist--skewed. These structural similarities with T3 show that the conformation features required by the active hormone can still be maintained with methyl substitution. The observation that the halogen-free analogues have relatively high activity but extremely low protein binding affinity implies that the role of iodine in hormone transport and biological activity can be deifferentiated. These data suggest that the iodines enhance hormone--protein binding by virtue of their electronic, as well as steric, properties.

Distal conformation of thyroid hormones. Crystal and molecular structure of 3,5,3'-triiodo-L-thyronine methyl ester.

In the crystal structure of 3,5,3'-triiodo-L-thyronine methyl ester, the 3' -iodine is distal, i.e., away from the alanine bearing ring, and the overall conformation is cisoid, that is, the alanine moiety and the outer phenyl ring lie on the same side of the inner phenyl ring plane. This conformation, reported here, for the first time, is in contrast to the transoid conformation previously observed for thyroid hormone structures. The torsional angles between the diphenyl either linkages (theta and theta') are -108 and 33 degrees, respectively, while the C-O-C angle is 117 degrees. The value of chi1, which describes the amino acid backbone conformation, is 308 degrees. The structure crystallizes in the tetragonal space group P41 with a = 8.225 (5) and c = 28.42 (1) A. The final R index is 0.06.

Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists.

Conformational analyses have been performed on several phenothiazine and thioxanthene dopamine antagonists using the MM2-87 program and parameter set. The compounds that were examined are thioridazine (2), methotrimeprazine (3), cis- and trans-chlorprothixene, and a piperidylidene derivative of chlorprothixene. In addition, (+)-2 and (-)-3 were determined by X-ray crystallography to have the R absolute configuration. The above compounds were superimposed onto loxapine, which was used as a template for the previously proposed dopamine D2 receptor ligand model. The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model. For example, a conformer of (+)-R-2 that is consistent with the ligand model is lower in energy than a consistent conformer for (-)-S-2, which agrees with the higher D2 receptor affinity of the former. Similarly, in agreement with the much higher affinity of (-)-R-3 relative to (+)-S-3, only the former contains a low energy conformer consistent with the ligand model. The ligand model is also consistent with the greater potency of cis-thioxanthenes over the trans isomers. These results emphasize the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor. The pharmacophore for D2 receptor ligands is compared with a recently proposed pharmacophore for D1 ligands.

Molecular conformation of ammonium 8-anilino-1-naphthalenesulfonate hemihydrate. A fluorescent probe for thyroxine binding to thyroxine binding globulin.

The crystal and molecular structure of the ammonium hemihydrate salt of the fluorescent dye, 8-anilino-1-naphthalenesulfonic acid (ANS), has been determined. There are two conformationally distinct molecules in the triclinic P1 lattice. The anilino nitrogen of one molecule has slightly distorted planar geometry, and the overall conformation of the molecule is similar to that observed for the potassium salt of the fluorescent dye 2-p-toluidinyl-6-naphthalenesulfonic acid (TNS). The anilino nitrogen of the other molecule has slightly distorted tetrahedral geometry and the overall conformation of the molecule is similar to that observed for the thyroid hormones T3 and T4. The observation of two distinct conformational modifications of ANS in this crystal structure determination has shed light on the conformational flexibility of the ANS molecule itself and on the mode by which its acts as a competitive inhibitor in thyroid hormone transport proteins and as a signal for hydrophobic areas in macromolecular systems.

Molecular structures of 2,4-diaminopyrimidine antifolates with antineoplastic activity.

2,4-Diamino-5-(1-adamantyl)-6-methylpyrimidine (DAMP) and its ethanesulfonate salt (DAMP-ES) are potent inhibitors of mammalian dihydrofolate reductase and also inhibit the growth of cultured cells as effectively as the drug methotrexate (MTX). DAMP is currently in phase I clinical studies. An analogue of DAMP having 5-(1-naphthyl) in place of the adamantyl group (DNMP) possesses little cytotoxic as well as enzyme inhibitory activity. The crystal and molecular structures of DAMPM-ES and DNMP were determined in order to elucidate the conformational aspects of drug specificity. The molecular conformation of DAMP-ES shows that the C8--C7 bond of the adamantyl ring is nearly coplanar with the pyrimidine ring (C8--C7--C5--C6 = 7.5 degrees) instead of staggered as expected from steric considerations. As a result, the pyrimidine ring and its 4,6-substituents are severely distorted from coplanarity. In DNMP, the 1-naphthalene ring is perpendicular to the pyrimidine ring (C8--C7--C5--C6 = -87.0 degrees) which is itself planar. N1 is protonated in DAMP-ES but not in DNMP. When the two structures are compared, the 5-substituents occupy different regions of space, with the outer ring of the naphthalene group outside of the volume occupied by the adamantyl ring. Therefore, the reduced effectiveness of DNMP may be caused by the inability of the naphthalene to fit the binding site in dihydrofolate reductase. This is the situation when DNMP is placed in the methotrexate binding site of Lactobacillus casei crystal structure.

Conformational analysis of antineoplastic antifolates: the crystal structure of trimetrexate and the aminopterine derivative 4-[N-[(2,4-diamino-6-pteridinyl)methyl]amino]benzoic acid.

The crystal structures of trimetrexate (TMQ) (2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoli ne) and 4-[N-[(2,4-diamino-6-pteridinyl)methyl]amino]benzoic acid (PMAB) were determined to examine their conformational features with respect to the enzyme-bound form of methotrexate (MTX). TMQ and MTX are antineoplastic drugs that act by inhibiting the enzyme dihydrofolate reductase. The molecular conformation of TMQ is extended with the trimethoxyanilino ring twisted 89 degrees from the quinazoline plane, and the molecular conformation of PMAB is completely planar. The geometry of the 2,4-diaminopteridine and 2,4-diaminoquinazoline rings are sensitive to protonation, and both TMQ and PMAB have geometries characteristic to a free base. TMQ crystallizes as a dimethyl sulfoxide hydrate. The quinazoline ring forms an antiparallel stacking arrangement in the lattice and forms a network of N...O hydrogen bonds with the solvent molecules. In PMAB there are both pteridine-benzoic acid (N...O) hydrogen bonds and pteridine-pteridine (N...N) hydrogen bonds. Although the molecular conformation of TMQ and PMAB differ from enzyme-bound MTX, rotational energy barriers calculated using CAMSEQ indicate that they can adopt a similar conformation to that seen for MTX complexed with dihydrofolate reductase. These energy calculations show that PMAB is quite flexible and further suggest that the 5-methyl in TMQ reduces its conformational flexibility in a different manner than the N(10)-methyl in MTX. These structural data also show that full geometry optimization and proper parameterization of electronic effects at N(10) are required to accurately represent antifolate conformational preferences for enzyme binding.

Molecular structure of thyroxine analogues. Crystal structure of 3,5,3'-triiodothyroacetic and 3,5,3',5'-tetraoiodothyroacetic acid N-diethanolamine (1:1) complexes.

Crystallographic data demonstrated that conformations of thyroid hormones and their derivatives in which the phenyl rings are either skewed (phi,phi'; +/-90,0 degrees) or twist-skewed (phi,phi'; +/-108, +/-28 degrees) are energetically favored. Acetic acid metabolites are consistently observed in the skewed conformation whereas their parent hormones are observed in the twist-skewed conformation. These preferences are manifestations of long-range conformational transmission and together with plasma protein binding data may indicate a site-specific preference for the skewed vs. twist-skewed conformation. These findings result in part from the crystal structure determinations of the N-diethanolamine (1:1) complexes of the active thyroxine metabolites 3,5,3'-triiodothyroacetic acid (T3AA) and 3,5,3'5'-tetraiodothyroacetic acid (T4AA) which are reported here. The conformation of the 3'-iodine in the hypocholestermic agent T3AA is distal, the biologically preferred conformation, and the overall conformation of T3AA is transoid, while that of T4AA is cisoid.