2N35
Fusion to a Highly Stable Consensus Albumin Binding Domain Allows for Tunable Pharmacokinetics
Summary for 2N35
| Entry DOI | 10.2210/pdb2n35/pdb |
| Related | 1GAB 2FS1 |
| NMR Information | BMRB: 25634 |
| Descriptor | Albumin binding protein (1 entity in total) |
| Functional Keywords | albumin binding domain, three-helix bundle, de novo protein |
| Biological source | synthetic construct |
| Total number of polymer chains | 1 |
| Total formula weight | 5863.73 |
| Authors | Gibbs, A.C.,Jacobs, S.A. (deposition date: 2015-05-21, release date: 2015-09-02, Last modification date: 2024-05-15) |
| Primary citation | Jacobs, S.A.,Gibbs, A.C.,Conk, M.,Yi, F.,Maguire, D.,Kane, C.,O'Neil, K.T. Fusion to a highly stable consensus albumin binding domain allows for tunable pharmacokinetics. Protein Eng.Des.Sel., 28:385-393, 2015 Cited by PubMed Abstract: A number of classes of proteins have been engineered for high stability using consensus sequence design methods. Here we describe the engineering of a novel albumin binding domain (ABD) three-helix bundle protein. The resulting engineered ABD molecule, called ABDCon, is expressed at high levels in the soluble fraction of Escherichia coli and is highly stable, with a melting temperature of 81.5°C. ABDCon binds human, monkey and mouse serum albumins with affinity as high as 61 pM. The solution structure of ABDCon is consistent with the three-helix bundle design and epitope mapping studies enabled a precise definition of the albumin binding interface. Fusion of a 10 kDa scaffold protein to ABDCon results in a long terminal half-life of 60 h in mice and 182 h in cynomolgus monkeys. To explore the link between albumin affinity and in vivo exposure, mutations were designed at the albumin binding interface of ABDCon yielding variants that span an 11 000-fold range in affinity. The PK properties of five such variants were determined in mice in order to demonstrate the tunable nature of serum half-life, exposure and clearance with variations in albumin binding affinity. PubMed: 26275855DOI: 10.1093/protein/gzv040 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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