- Course overview
- Search within this course
- Introduction to public genetic variation data
- Case study 1: variants in a gene (PKD1)
- Cast study 2: Search for a variant (rs334)
- Case study 3: Search for a phenotype (non-melanoma skin cancer)
- Case study 4: Starting with the literature
- Your feedback
Comparing 2D and 3D structures
Suppose you want to explore the 2D and 3D structures of the hemoglobin subunit beta to understand how genetic variants influence the protein structure. You can do this by clicking on the name of this macromolecule, i.e. Hemoglobin subunit beta. This will take you through to the macromolecules page for that specific structure (Figure 12). Here you are presented with sequence views for that particular protein, as well a 2D topology graphic and a 3D structure viewer. The first section in the sequence view (Molecule) shows any sequence annotations for the protein in this structure, with these highlighted in orange (1D sequence annotation). Hovering over the orange bar for this example will display the change of residue 6 from glutamate (E) to valine (V) as is the case for sickle cell hemoglobin variants.
Figure 12 The macromolecules page for haemoglobin subunit beta. This is an interactive subsection of the orginal page which can be viewed in PDBe.
If you hover over residue 6 in the schematic of the Topology 2D diagram, you will find that this specific amino acid is highlighted in yellow on the surface of the hemoglobin molecule in the 3D structure view.
The change of this amino acid in the sickle cell variant is from a hydrophilic residue (glutamate) to a hydrophobic residue (valine). This change generates a ‘sticky patch’ on the surface of the protein because the ‘water loving’ amino acid has been swapped for a ‘water hating’ one. This causes the association of multiple hemoglobin complexes, via this hydrophobic valine residue. This consequently leads to the aggregation of hemoglobin molecules into fibres, therefore producing cells with the sickle phenotype that is observed for this variant1. From this example you can see that by looking at the structure and understanding the type of variation involved, you can begin to draw functional conclusions about the consequences of variation.