Therefore, the aim of this study was to determine the quaternary structure of DHDPS from the agriculturally-important species, Vitis vinifera or the common grapevine. Here, we present a thorough characterization of the structure of Vv-DHDPS both in aqueous solution and the crystal state compared to BaDHDPS, an example of the typical bacterial tetramer. We show that Vv-DHDPS adopts a ‘back-to-back’ dimer-of-dimers consistent with the structure reported for N. sylvestris DHDPS, and subsequently demonstrate using molecular dynamics simulations that the ‘back-to-back’ architecture is important for stabilizing protein dynamics of the ‘tight’ dimer unit. This study suggests that DHDPS from plants adopt an alternative quaternary architecture to the typical bacterial form, thus offering insight into the molecular evolution of an important oligomeric enzyme. In our study of targeted sequencing of coding and conserved portions of the UMOD gene region, we did not identify any common non-synonymous coding variant that could account for the GWAS signal by itself. Rare variants were identified and verified, but they were not significantly enriched among individuals at the extremes of THP levels when the entire study population was considered. The V458L variant, which is predicted to have a AP24534 Src-bcr-Abl inhibitor damaging effect on protein function, showed significant association with eGFR in one but not both studies, association with THP, and no apparent effect in functional studies on protein aggregation or trafficking as observed for monogenic diseasecausing variants. Several previous studies have re-sequenced candidate genes identified through GWAS in order to identify novel rare genetic variants with potentially stronger associations with the phenotype than observed for the trait-associated variants in GWAS. More successful recent examples in the area of common, complex diseases include uric acid and gout and inflammatory bowel disease. Using 350 cases of Crohn’s disease and controls, investigators were able to identify multiple independent rare variants in 7 genes, some with large effect sizes. Similar to the present study, the variants identified did not account for the original GWAS signal. However, less success has been observed for many other common complex diseases, including fine-mapping of the 9p21 region in association with type 2 diabetes and coronary artery disease, and type 1 diabetes. There are currently many ongoing sequencing efforts that are focused on sequencing the exons of candidate genes, as well as whole-exome sequencing. The relative yield of this approach, as compared to whole genome sequencing and assessment of structural variation, remains unknown. Melancholic depression is a subtype of major depressive disorder that encompasses a constellation of distinctive clinical features such as anhedonia, distinct quality of mood and mood non-reactivity, psychomotor disturbances, feelings of guilt, early awakening, diurnal variation and anorexia. Specific neurobiological correlates such as cortisol dysregulation and altered sleep patterns have also been appreciated in melancholia.