Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 Å resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG-which possesses the highest affinity-establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.

This study shows that an educational intervention applied at the site of primary care can result in significant improvements in patient asthma outcomes and reduce unscheduled visits and inappropriate use of medications such as antibiotics.

The aldo-keto reductase (AKR) human type 3 3a-hydroxysteroid dehydrogenase (h3a-HSD3, AKR1C2) plays a crucial role in the regulation of the intracellular concentrations of testosterone and 5a-dihydrotestosterone (5a-DHT), two steroids directly linked to the etiology and the progression of many prostate diseases and cancer. This enzyme also binds many structurally different molecules such as 4-hydroxynonenal, polycyclic aromatic hydrocarbons, and indanone. To understand the mechanism underlying the plasticity of its substrate-binding site, we solved the binary complex structure of h3a-HSD3-NADP(H) at 1.9 Å resolution. During the refinement process, we found acetate and citrate molecules deeply engulfed in the steroid-binding cavity. Superimposition of this structure with the h3a-HSD3-NADP(H)-testosterone/ acetate ternary complex structure reveals that one of the mobile loops forming the binding cavity operates a slight contraction movement against the citrate molecule while the side chains of many residues undergo numerous conformational changes, probably to create an optimal binding site for the citrate. These structural changes, which altogether cause a reduction of the substrate-binding cavity volume (from 776 Å 3 in the presence of testosterone/acetate to 704 Å 3 in the acetate/citrate complex), are reminiscent of the ''induced-fit'' mechanism previously proposed for the aldose reductase, another member of the AKR superfamily. We also found that the replacement of residues Arg 301 and Arg 304 , localized near the steroid-binding cavity, significantly affects the 3a-HSD activity of this enzyme toward 5a-DHT and completely abolishes its 17b-HSD activity on 4-dione. All these results have thus been used to reevaluate the binding mode of this enzyme for androgens.Keywords: aldo-keto reductase; hydroxysteroid dehydrogenase; crystal structure; induced-fit mechanism 'Universite´Laval, 2705, boul. Laurier, Ste-Foy, QC, G1V 4G2, Canada; e-mail: rock.breton@crchul.ulaval.ca; fax: (418) 654-2761.Abbreviations: h3a-HSD3, human 3a-hydroxysteroid dehydrogenase type 3; h20a-HSD, human 20a-hydroxysteroid dehydrogenase; h3a-HSD1, human 3a-hydroxysteroid dehydrogenase type 1; 17b-HSD, 17b-hydroxysteroid dehydrogenase; NADP(H), reduce form of nicotinamide adenine dinucleotide phosphate; GST, glutathione sulfotransferase; PDB, Protein Data Bank; AKR, aldo-keto reductase; progesterone, 5-pregnen-3,20-dione; 4-dione, 4-androsten-3,20-dione; PAH, polycyclic aromatic hydrocarbon; EDTA, ethylene diamine tetraacetic acid.Article and publication are at

The objective of this study is to evaluate whether a chronic obstructive pulmonary disease (COPD) self-management education program with coaching of a case manager improves patient-related outcomes and leads to practice changes in primary care. COPD patients from six family medicine clinics (FMCs) participated in a 1-year educational program offered by trained case managers who focused on treatment adherence, inhaler techniques, smoking cessation, and the use of an action plan for exacerbations. Health-care utilization, health-related quality of life (HRQL), treatment adherence, inhaler technique, and COPD knowledge were assessed at each visit with validated questionnaires. We also evaluated whether the use of spirometry and the assessment of individual patient needs led to a more COPD-targeted treatment by primary care physicians, based on changes in prescriptions for COPD (medication, immunization, and written action plan). Fifty-four patients completed the follow-up visits and were included in the analysis. The number of unscheduled physician visits went from 40 the year before intervention to 17 after 1 year of educational intervention (p = 0.033). Emergency room visits went from five to two and hospitalizations from two to three (NS). Significant improvements were observed in HRQL (p = 0.0001), treatment adherence (p = 0.025), adequate inhaler technique (p < 0.0001), and COPD knowledge (p < 0.001). Primary care physicians increased their prescriptions for long-acting bronchodilators with/without inhaled corticosteroid, flu immunizations, and COPD action plans in the event patient had an exacerbation. The COPD self-management educational intervention in FMCs reduced unscheduled visits to the clinic and improved patients’ quality of life, self-management skills, and knowledge. The program had a positive impact on COPD-related practices by primary care physicians in the FMCs.

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