Structural basis for the interaction of human ß-defensin 6 and its putative chemokine receptor CCR2 and breast cancer microvesicles.
J Mol Biol
; 425(22): 4479-95, 2013 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-23938203
Human ß-defensins (hBDs) are believed to function as alarm molecules that stimulate the adaptive immune system when a threat is present. In addition to its antimicrobial activity, defensins present other activities such as chemoattraction of a range of different cell types to the sites of inflammation. We have solved the structure of the hBD6 by NMR spectroscopy that contains a conserved ß-defensin domain followed by an extended C-terminus. We use NMR to monitor the interaction of hBD6 with microvesicles shed by breast cancer cell lines and with peptides derived from the extracellular domain of CC chemokine receptor 2 (Nt-CCR2) possessing or not possessing sulfation on Tyr26 and Tyr28. The NMR-derived model of the hBD6/CCR2 complex reveals a contiguous binding surface on hBD6, which comprises amino acid residues of the α-helix and ß2-ß3 loop. The microvesicle binding surface partially overlaps with the chemokine receptor interface. NMR spin relaxation suggests that free hBD6 and the hBD6/CCR2 complex exhibit microsecond-to-millisecond conformational dynamics encompassing the CCR2 binding site, which might facilitate selection of the molecular configuration optimal for binding. These data offer new insights into the structure-function relation of the hBD6-CCR2 interaction, which is a promising target for the design of novel anticancer agents.
Palavras-chave
2D; BN; Blue Native; CCR2; CSP; HSQC; MV; NMR; NOE; NOESY; PDB; PS; Protein Data Bank; TOCSY; backbone dynamics; chemical shift perturbation; hBD; heteronuclear single quantum coherence; human ß-defensin; innate immune system; microvesicle; nuclear Overhauser effect; nuclear Overhauser effect spectroscopy; phosphatidylserine; total correlated spectroscopy; two-dimensional; ß-defensin
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta-Defensinas
/
Receptores CCR2
Limite:
Female
/
Humans
Idioma:
En
Revista:
J Mol Biol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Holanda