TY - JOUR

T1 - GluVII:06--a highly conserved and selective anchor point for non-peptide ligands in chemokine receptors

AU - Rosenkilde, Mette M

AU - Schwartz, Thue W

N1 - Keywords: Amino Acid Sequence; Animals; Binding Sites; Drug Design; Glutamic Acid; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Molecular Structure; Receptors, Chemokine; Sequence Alignment; Structure-Activity Relationship

PY - 2006

Y1 - 2006

N2 - A majority of small molecule non-peptide ligands for chemokine receptors in general are characterized by the presence of one or two centrally located, positively charged nitrogen atoms and these compounds are also often of relatively similar elongated overall structure with terminal aromatic moieties. In the corresponding main ligand-binding crevice of the chemokine 7TM receptors is found a centrally located glutamic acid residue in position 6 of transmembrane segment VII in 74% of the chemokine receptors but only in approx. 1% of non-chemokine receptors. GluVII:06 has been demonstrated to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule ligands and that the two peripheral chemical moieties of the ligands from this central point in the receptor structure explore each of the two halves of the main ligand binding pocket. It is envisioned that knowledge of this binding mode can be exploited in structure-based discovery and design of novel chemokine receptor ligands and especially ligands with specifically optimized properties.

AB - A majority of small molecule non-peptide ligands for chemokine receptors in general are characterized by the presence of one or two centrally located, positively charged nitrogen atoms and these compounds are also often of relatively similar elongated overall structure with terminal aromatic moieties. In the corresponding main ligand-binding crevice of the chemokine 7TM receptors is found a centrally located glutamic acid residue in position 6 of transmembrane segment VII in 74% of the chemokine receptors but only in approx. 1% of non-chemokine receptors. GluVII:06 has been demonstrated to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule ligands and that the two peripheral chemical moieties of the ligands from this central point in the receptor structure explore each of the two halves of the main ligand binding pocket. It is envisioned that knowledge of this binding mode can be exploited in structure-based discovery and design of novel chemokine receptor ligands and especially ligands with specifically optimized properties.

M3 - Journal article

C2 - 16918451

VL - 6

SP - 1319

EP - 1333

JO - Current Topics in Medicinal Chemistry

JF - Current Topics in Medicinal Chemistry

SN - 1568-0266

IS - 13

ER -