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Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites

Nature Structural Biology volume 5, pages 827–835 (1998)Cite this article

Abstract

Human serum albumin (HSA) is the most abundant protein in the circulatory system. Its principal function is to transport fatty acids, but it is also capable of binding a great variety of metabolites and drugs. Despite intensive efforts, the detailed structural basis of fatty acid binding to HSA has remained elusive. We have now determined the crystal structure of HSA complexed with five molecules of myristate at 2.5 Å resolution. The fatty acid molecules bind in long, hydrophobic pockets capped by polar side chains, many of which are basic. These pockets are distributed asymmetrically throughout the HSA molecule, despite its symmetrical repeating domain structure.

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Figure 1: Domain structure of HSA and location of myristate and TIB binding sites.
Figure 2: The distribution of myristate binding sites is highly asymmetric despite the structural homologies between domains of HSA.
Figure 3: Stereo diagram of the simulated annealing Fo - Fc omit map contoured at 2.75σ, showing difference electron density (grey) for Myr 3 and Myr 4 bound within sub-domain IIIA (blue).
Figure 4: Superposition of unliganded HSA (PDB code 1ao6) and HSA−myristate reveals the dramatic nature of the conformational change that occurs upon binding of the fatty acid.
Figure 5: a, Superposition of sub-domains IIIA and IIIB highlights the similarities and differences in secondary structure and demonstrates that they bind myristate in quite disparate configurations.
Figure 6: Binding interactions for TIB1 and Myr 2 in sub-domain IIA.

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Acknowledgements

We are very grateful to Delta Biotechnology Ltd. for providing all of the recombinant HSA used in this study. We thank A. Bhattacharya and the staff at both the Synchrotron Radiation Source, Daresbury Laboratory and at DESY, Hamburg for their assistance in data collection.

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  1. Blackett Laboratory, Imperial College, London, SW7 2BZ, Prince Consort Road, UK

    Stephen Curry, Hendrik Mandelkow, Peter Brick & Nick Franks

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  1. Stephen Curry
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  2. Hendrik Mandelkow
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Correspondence to Stephen Curry.

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Curry, S., Mandelkow, H., Brick, P. et al. Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nat Struct Mol Biol 5, 827–835 (1998). https://doi.org/10.1038/1869

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