Community Research and Development Information Service - CORDIS

Crystallography aids drug design

Crystallography is a powerful method for understanding the 3D structure of molecules. A European study utilised this technique to aid the design of drugs.
Crystallography aids drug design
Hypercholesterolaemia is a condition associated with excess blood levels of low-density lipoprotein (LDL). LDL has a strong propensity to accumulate in the arterial walls and promote atherosclerosis and, as a result, it is considered as a factor associated with coronary heart disease. The LDL plasma levels are regulated by endocytosis of LDL after binding to the ARH adaptor protein.

The oxidised form of LDL (OxLDL) is considered a causative pathogenic factor directly triggering the inflammation process in the development of atherosclerosis. However, since LDL is a multicomponent assembly of proteins and lipids, the chemical identity and structural properties of OxLDL are not clear.

Scientists on the EU-funded CHOLESTRUCTURE (Regulation of cholesterol homeostasis by the ARH-mediated endocytosis of the LDL receptor) project set out to study the mechanism of ARH function using biochemical and structural tools. Towards this goal, they expressed ARH in bacteria together with its putative binding partner, the clathrin adaptor AP-2. However, aggregation issues prohibited the crystallisation of the receptor and steered scientists down a different scientific path.

In this context, they proceeded with characterisation of the different OxLDL forms. For this purpose, they used X-ray crystallography to capture the atherogenic forms of LDL using antibodies developed to recognise it. Given the involvement of OxLDL in the development of atherosclerosis, identification of the pathogenic part of LDL is of fundamental clinical importance. This information will lead to the development and improvement of neutralising factors of therapeutic value.

In another part of the project, the crystallography expertise of the scientific teams helped to study the fungal CFEM protein. These virulence factors are responsible for extracting iron from haemoglobin and delineation of their 3D structure should facilitate drug design approaches to battle fungal diseases. Similarly, structure determination of a pathogenic bacterial tyrosine kinase served as a basis for the design of small therapeutic molecules.

Collectively, work in the CHOLESTRUCTURE study illustrated the capacity of crystallography structural information to foster the design of new drugs.

Related information

Keywords

Crystallography, drug design, LDL, atherosclerosis
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