1YIL

Structure of Hen egg white lysozyme soaked with Cu2-Xylylbicyclam

Summary for 1YIL

• Entry DOI: 10.2210/pdb1yil/pdb
• Descriptor: Lysozyme C, CHLORIDE ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: Gallus gallus (chicken)
• Cellular location: Secreted: P00698
• Total number of polymer chains: 1
• Total formula weight: 15684.80

Authors

Hunter, T.M.,McNae, I.W.,Liang, X.,Bella, J.,Parsons, S.,Walkinshaw, M.D.,Sadler, P.J. (deposition date: 2005-01-12, release date: 2005-02-08, Last modification date: 2024-10-30)

Primary citation

Hunter, T.M.,McNae, I.W.,Liang, X.,Bella, J.,Parsons, S.,Walkinshaw, M.D.,Sadler, P.J.
Protein recognition of macrocycles: binding of anti-HIV metallocyclams to lysozyme
Proc.Natl.Acad.Sci.Usa, 102:2288-2292, 2005

PubMed Abstract: The macrocyclic antiviral drug xylyl-bicyclam blocks entry of HIV into cells by targeting the CXCR4 coreceptor, a seven-helix transmembrane G-protein-coupled receptor. Its affinity for CXCR4 is enhanced by binding to Cu2+, Ni2+, or Zn2+. Metallocyclams have a rich configurational chemistry and proteins may bind selectively to specific metallocyclam configurations. Our studies of lysozyme reveal structural details of protein-metallocyclam interactions that are important for receptor recognition. Solution NMR studies show that Cu-cyclam interacts with specific tryptophan residues of lysozyme (Trp-62, Trp-63, and Trp-123). Two major binding sites for both Cu-cyclam and Cu2-xylyl-bicyclam were detected by x-ray crystallography. In the first site, Cu2+ in one cyclam ring of Cu2-xylyl-bicyclam adopts a trans configuration and is coordinated to a carboxylate oxygen of Asp-101, whereas for Cu-cyclam two ring NH groups form H bonds to the carboxylate oxygens of Asp-101, stabilizing an unusual cis (folded) cyclam configuration. For both complexes in this site, a cyclam ring is sandwiched between the indole side chains of two tryptophan residues (Trp-62 and Trp-63). In the second site, a trans cyclam ring is stacked on Trp-123 and H bonded to the backbone carbonyl of Gly-117. We show that there is a pocket in a model of the human CXCR4 coreceptor in which trans and cis configurations of metallobicyclam can bind by direct metal coordination to carboxylate side chains, cyclam-NH...carboxylate H bonding, together with hydrophobic interactions with tryptophan residues. These studies provide a structural basis for the design of macrocycles that bind stereospecifically to G-coupled and other protein receptors.

PubMed: 15701702
DOI: 10.1073/pnas.0407595102

Experimental method

X-RAY DIFFRACTION (1.6 Å)