Biology Reference
In-Depth Information
Figure 4. Ribbon depiction of the complex between the extracellular domain of rHuEPO and an ago-
nist peptide. The X-ray crystallographic structure of rHuEPOR complexed with an agonist peptide
was resolved by Livnah et al. [10]. The two-fold symmetry of the peptide allows the dimerization of
two EPOR. The functional mimicry of EPO by a 20-residue peptide with a totally unrelated sequence
was of considerable value in understanding the structure of the receptor and its signal transduction
mechanisms.
The interface between the peptide and EPOR is mainly hydrophobic in
nature with very few invaginations and charged residues that would be charac-
teristic of a naturally occurring binding pocket. The three residues contributing
the most binding energy on the receptor to EMP1 are Phe93, Met150, and
Phe205. These amino acids contact Phe10 and Tyr4 of the peptide. The dimer-
ic and symmetrical nature of the peptide is reflected in the nature of the bind-
ing interaction with EPOR. Both interaction sites on the EMP1 dimer are iden-
tical; therefore, the two receptors adopt orientations that are different than ori-
entations found in EPOR dimerized by rHuEPO. If the two complexes
(rHuEPO/EPOR and EMP1/EPOR) are viewed along a plane that is perpendi-
cular to the membrane, almost a 60° difference is seen between the angles of
the D1 domain of EPOR with respect to the rHuEPO and peptide complexes. In
addition, a significant difference of about 45° in the angle of the hinge region
is seen between D1 and D2 with respect to the binding of rHuEPO and EMP1.
Conclusion
Perhaps what is most surprising in this body of research is the number of dif-
ferent molecules that can effect the dimerization and signal transduction of
