TY - JOUR

T1 - Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

AU - Rosenkilde, M M

AU - Kledal, T N

AU - Bräuner-Osborne, Hans

AU - Schwartz, T W

PY - 1999/1/8

Y1 - 1999/1/8

N2 - A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74 receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling, whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc switch through introduction of two His residues at the extracellular end of transmembrane segment V enabled Zn2+ to act as a prototype non-peptide inverse agonist, which eliminated the constitutive signaling. It is concluded that ORF-74, which is believed to be causally involved in the formation of highly vascularized tumors, has been optimized for agonist and inverse agonist modulation by the endogenous angiogenic GRO peptides and angiostatic IP-10 and stromal cell-derived factor-1alpha, respectively. ORF-74 could serve as a target for the development of non-peptide inverse agonist drugs as demonstrated by the effect of Zn2+ on the metal ion site-engineered receptor.

AB - A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74 receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling, whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc switch through introduction of two His residues at the extracellular end of transmembrane segment V enabled Zn2+ to act as a prototype non-peptide inverse agonist, which eliminated the constitutive signaling. It is concluded that ORF-74, which is believed to be causally involved in the formation of highly vascularized tumors, has been optimized for agonist and inverse agonist modulation by the endogenous angiogenic GRO peptides and angiostatic IP-10 and stromal cell-derived factor-1alpha, respectively. ORF-74 could serve as a target for the development of non-peptide inverse agonist drugs as demonstrated by the effect of Zn2+ on the metal ion site-engineered receptor.

KW - 3T3 Cells

KW - Amino Acid Sequence

KW - Animals

KW - COS Cells

KW - Chemokines

KW - Herpesvirus 8, Human

KW - Membrane Proteins

KW - Mice

KW - Molecular Sequence Data

KW - Open Reading Frames

KW - Receptors, Chemokine

KW - Sequence Homology, Amino Acid

KW - Signal Transduction

KW - Viral Proteins

KW - Zinc

M3 - Journal article

C2 - 9873037

VL - 274

SP - 956

EP - 961

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -