6M5E

Human serum albumin with cyclic peptide dalbavancin

Summary for 6M5E

• Entry DOI: 10.2210/pdb6m5e/pdb
• Descriptor: Serum albumin, dalbavancin, O-(O-(2-AMINOPROPYL)-O'-(2-METHOXYETHYL)POLYPROPYLENE GLYCOL 500), ... (10 entities in total)
• Functional Keywords: transporter, cyclic peptide, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 212694.60

Authors

Ito, S.,Senoo, A.,Nagatoishi, S.,Ohue, M.,Yamamoto, M.,Tsumoto, K.,Wakui, N. (deposition date: 2020-03-10, release date: 2020-11-18, Last modification date: 2023-11-29)

Primary citation

Ito, S.,Senoo, A.,Nagatoishi, S.,Ohue, M.,Yamamoto, M.,Tsumoto, K.,Wakui, N.
Structural Basis for the Binding Mechanism of Human Serum Albumin Complexed with Cyclic Peptide Dalbavancin.
J.Med.Chem., 63:14045-14053, 2020

PubMed Abstract: Cyclic peptides, with unique structural features, have emerged as new candidates for drug discovery; their association with human serum albumin (HSA; long blood half-life) is crucial to improve drug delivery and avoid renal clearance. Here, we present the crystal structure of HSA complexed with dalbavancin, a clinically used cyclic peptide. Small-angle X-ray scattering and isothermal titration calorimetry experiments showed that the HSA-dalbavancin complex exists in a monomeric state; dalbavancin is only bound to the subdomain IA of HSA in solution. Structural analysis and MD simulation revealed that the swing of Phe70 and movement of the helix near dalbavancin were necessary for binding. The flip of Leu251 promoted the formation of the binding pocket with an induced-fit mechanism; moreover, the movement of the loop region including Glu60 increased the number of noncovalent interactions with HSA. These findings may support the development of new cyclic peptides for clinical use, particularly the elucidation of their binding mechanism to HSA.

PubMed: 33183011
DOI: 10.1021/acs.jmedchem.0c01578

Experimental method

X-RAY DIFFRACTION (2.8 Å)