4K71

Crystal structure of a high affinity Human Serum Albumin variant bound to the Neonatal Fc Receptor

Summary for 4K71

• Entry DOI: 10.2210/pdb4k71/pdb
• Descriptor: Serum albumin, IgG receptor FcRn large subunit p51, Beta-2-microglobulin, ... (5 entities in total)
• Functional Keywords: mhc class i, lipid transport, endosome recycling, endosome
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P02768 P61769; Cell membrane; Single-pass type I membrane protein (By similarity): P55899
• Total number of polymer chains: 6
• Total formula weight: 219084.02

Authors

Schmidt, M.M.,Townson, S.A.,Andreucci, A.,Dombrowski, C.,Erbe, D.V.,King, B.,Kovalchin, J.T.,Masci, A.,Murillo, A.,Schirmer, E.B.,Furfine, E.S.,Barnes, T.M. (deposition date: 2013-04-16, release date: 2013-10-23, Last modification date: 2014-02-05)

Primary citation

Schmidt, M.M.,Townson, S.A.,Andreucci, A.J.,King, B.M.,Schirmer, E.B.,Murillo, A.J.,Dombrowski, C.,Tisdale, A.W.,Lowden, P.A.,Masci, A.L.,Kovalchin, J.T.,Erbe, D.V.,Wittrup, K.D.,Furfine, E.S.,Barnes, T.M.
Crystal structure of an HSA/FcRn complex reveals recycling by competitive mimicry of HSA ligands at a pH-dependent hydrophobic interface.
Structure, 21:1966-1978, 2013

PubMed Abstract: The long circulating half-life of serum albumin, the most abundant protein in mammalian plasma, derives from pH-dependent endosomal salvage from degradation, mediated by the neonatal Fc receptor (FcRn). Using yeast display, we identified human serum albumin (HSA) variants with increased affinity for human FcRn at endosomal pH, enabling us to solve the crystal structure of a variant HSA/FcRn complex. We find an extensive, primarily hydrophobic interface stabilized by hydrogen-bonding networks involving protonated histidines internal to each protein. The interface features two key FcRn tryptophan side chains inserting into deep hydrophobic pockets on HSA that overlap albumin ligand binding sites. We find that fatty acids (FAs) compete with FcRn, revealing a clash between ligand binding and recycling, and that our high-affinity HSA variants have significantly increased circulating half-lives in mice and monkeys. These observations open the way for the creation of biotherapeutics with significantly improved pharmacokinetics.

PubMed: 24120761
DOI: 10.1016/j.str.2013.08.022

Experimental method

X-RAY DIFFRACTION (2.4 Å)