Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone–receptor interactions

AbstractBackground: Glycoprotein hormones influence the development and function of the ovary, testis and thyroid by binding to specific high-affinity receptors. The extracellular domains of these receptors are members of the leucine-rich repeat (LRR) protein superfamily and are responsible for the high-affinity binding. The crystal structure of a glycoprotein hormone, namely human choriogonadotropin (hCG), is known, but neither the receptor structure, mode of hormone binding, nor mechanism for activation, have been established.Results Despite very low sequence similarity between exon-demarcated LRRs in the receptors and the LRRs of porcine ribonuclease inhibitor (RI), the secondary structures for the two repeat sets are found to be alike. Constraints on curvature and β-barrel geometry from the sequence pattern for repeated βα units suggest that the receptors contain three-dimensional structures similar to that of RI. With the RI crystal structure as a template, models were constructed for exons 2–8 of the receptors. The model for this portion of the choriogonadotropin receptor is complementary in shape and electrostatic characteristics to the surface of hCG at an identified focus of hormone–receptor interaction.Conclusion The predicted models for the structures and mode of hormone binding of the glycoprotein hormone receptors are to a large extent consistent with currently available biochemical and mutational data. Repeated sequences in β-barrel proteins are shown to have general implications for constraints on structure. Averaging techniques used here to recognize the structural motif in these receptors should also apply to other proteins with repeated sequences

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Polar intermolecular interactions encoded in partition-coefficients :an indirect estimation of hydrogen-bond parameters of polyfunctional solutes

Lipophilicity (expressed as log P, the logarithm of partition coefficients) is known to be decomposable into a cavity/volume term V expressing mainly hydrophobic and dispersive solute-solvent interactions, and polar terms reflecting electrostatic solute-solvent interactions, e.g. log P = aV + b-pi* + c-alpha + d-beta, where pi*, alpha, and beta are solvatochromic parameters, i.e., the dipolarity/polarizability, H-bond donor acidity, and H-bond acceptor basicity, respectively. Here, we define a parameter LAMBDA such that LAMBDA = b-pi* + c-alpha + d-beta and show that LAMBDA(oct) (i.e., LAMBDA calculated from 1-octanol/water log P values) is correlated mainly with beta (r2 = 0.867; n = 168), while LAMBDA(alk) (i.e., LAMBDA-calculated from alkane/water log P values) is correlated mainly with alpha and beta (r2 = 0.897; n = 104). Thus, and within the explored range of values, a fair estimate of the H-bond donor acidity and acceptor basicity of solutes can be obtained from their log P(oct) and log P(alk) values and calculated molecular volume

Octan-1-Ol-water partition-coefficients of zwitterionic alpha-amino-acids - determination by centrifugal partition chromatography and factorization into steric hydrophobic and polar components

The distribution coefficients of free alpha-amino acids have been measured around their isoelectric value by centrifugal partition chromatography (CPC), allowing the determination of the partition coefficient (log P) of the amino acids in their zwitterionic form. Good correlations with published distribution coefficients of amino acid derivatives allowed log P values to be calculated for the five amino acids (Arg, Asn, Asp, Glu, Lys) whose high polarity prevented direct measurements by CPC. The log P values were factorized into a steric component (molecular volume V, mainly accounting for inductive and hydrophobic forces) and a polarity factor (LAMBDA, accounting for ion-dipole and dipole-dipole interactions and hydrogen-bonds) which correlates with other amino acid parameters expressing mainly polar interactions. Using two examples from the literature, we show that multiple linear regression analysis based on steric and polar parameters is able to afford a quantitative interpretation of factors influencing protein conformational stabilit

Structure lipophilicity relationships of zwitterionic amino-acids

The lipophilicity of zwitterionic amino acids was determined by measuring their distribution coefficients in an octan-1-ol-buffer system at pH values near their isoelectric point (log D(i)) using centrifugal partition chromatography (CPC). The observed differences in the lipophilic expression of methylene groups in the side-chain of alpha-amino acids are interpreted as a consequence of their different electronic structure and/or hydration features due to proximity effects exerted by the dipolar +H3N-CH-CO2- moiety. A comparison of non-additive log D(i) increments of methylene groups in a flexible alkyl and relatively rigid cycloalkyl side-chain of alpha-amino acids leads to the conclusion that the flexible alkyl side-chain is not fully accessible to solvents. The influence of intercharge distance on lipophilicity was examined with homologous piperidinyl carboxylic acids, indicating a decrease 0.4 log D(I) units per increase of 1 angstrom between opposite charges. Among flexible non-alpha-amino acids, an increase in lipophilicity increment is observed only when the seventh carbon is added between the two opposite charges. As for the lipophilicity of N-alkylated zwitterions, N,N-dimethylglycine is shown to be less lipophilic than N-methylglycine, a finding of potential interest in the context of metabolic reactions of N-dealkylation. It is postulated that amino acids are transferred into lipidic phases in the form of hydrates, implying that the latter may have biological significanc

Physicochemical properties and transport behavior of piribedil : considerations on its membrane-crossing potential

The lipophilicity (expressed by log P(oct)) and H-bond donor acidity (expressed by DELTA-log P(oct-hep)) of the dopaminergic agonist piribedil in different ionization states were investigated in order to assess its capacity for crossing membranes. The present study showed that piribedil has a relatively high lipophilicity (log P(oct) = 2.84) and is a non- or very weak H-bond donor (DELTA-log P(oct-hep) = 0.75), implying optimal properties for transmembranal transport. Based on its microscopic ionization behaviour as studied by C-13-NMR spectroscopy and (log P - log P+) value (5.04) (a measure of the stability of the ionic vs neutral species in a lipidic phase), protonation proved to be very unfavourable in water-saturated octanol due to the hindrance of solvation by the two bulky groups adjacent to the piperazinyl amino group. In addition, transport of piribedil across a lipophilic membrane was studied according to first-order kinetics in a three-compartment model. The effects of lipophilic counterions on the partitioning behaviour and transfer kinetics were examined and shown to be non-existent at equimolar concentration

Modeling of beta-adrenoceptors based on molecular electrostatic potential studies of agonists and antagonists

The molecular electrostatic potential (MEP) of 32 beta-adrenoceptor ligands, mainly antagonists, was calculated by the STO-3G ab initio quantum mechanical method. The MEP of phenylethanolamines (PEAs) features a negative minimum in the meta region (designated M1) which is topographically equivalent to a minimum (designated M2) found in the vicinity of the aromatic ring in all (aryloxy)propanolamines (AOPAs). In these compounds, a second negative zone located beyond the meta position and designated M3 is found in all beta 1-selective antagonists and in some nonselective and beta 2-selective antagonists. The beta 1-selective antagonists feature in the para position an additional zone which is positive (P4) in the full antagonists and negative (M4) in the antagonists displaying intrinsic sympathomimetic activity (ISA). The MEP-based pharmacophoric models of PEAs, AOPAs, and oxime ethers show common elements and lead to a proposed general model for beta-adrenoceptor ligands