Structural plasticity in a human blood transport protein

What is it about?

Afamin (AFM) is a human plasma glycoprotein and biomarker for metabolic syndrome that transports hydrophobic molecules. We obtained a high resolution structure of a new AFM crystal form, by controlled dehydration, which confirms that afamin is highly flexible and its domain arrangements significantly influence the shape of its binding site. Afamin seems to bind Gd-DO3A, a paramagnetic MRI contrast agent. Its relative albumin is known to bind Gd agents (but no structure is available, so afamin-Gd may serve as a surrogate). Against all odds, we were able to resurrect highly anisotropic and incomplete data with the Global Phasing StarAniso server. While the model suffers from absence of a large fraction of the C-terminal (but is surprisingly as ‘good’ as comparable PDB entries), it shows that even from abysmal and by historical judgement considered useless data, reasonable information supporting modest claims can be extracted.

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Why is it important?

The findings caution against inference of ligand binding properties from single crystal structures, particularly so when the molecule is a promiscuous transporter that has to adapt to various cargo. Given that the very same uncertainties exist in related albumin drug complexes and molecules with high plasticity in general, this is an important point to emphasize. The paper raises several general issues related to plasticity and dynamics that are becoming increasingly relevant for complex structure determinations and brings the debate on the usefulness of data quality metrics further into the literature.