Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL.
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Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL. / Jomain, Jean-Baptiste; Tallet, Estelle; Broutin, Isabelle; Hoos, Sylviane; van Agthoven, Jan; Ducruix, Arnaud; Kelly, Paul A; Kragelund, Birthe B; England, Patrick; Goffin, Vincent.
In: Journal of Biological Chemistry, Vol. 282, No. 45, 2007, p. 33118-31.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL.
AU - Jomain, Jean-Baptiste
AU - Tallet, Estelle
AU - Broutin, Isabelle
AU - Hoos, Sylviane
AU - van Agthoven, Jan
AU - Ducruix, Arnaud
AU - Kelly, Paul A
AU - Kragelund, Birthe B
AU - England, Patrick
AU - Goffin, Vincent
N1 - Keywords: Amino Acid Sequence; Animals; Cell Line; Circular Dichroism; Crystallography, X-Ray; Drug Design; Glycine; Heat; Humans; Kinetics; Models, Molecular; Molecular Sequence Data; Mutation; Prolactin; Protein Binding; Protein Denaturation; Protein Structure, Tertiary; Rats; Receptors, Prolactin; Structural Homology, Protein; Thermodynamics
PY - 2007
Y1 - 2007
N2 - Competitive antagonists of the human prolactin (hPRL) receptor are a novel class of molecules of potential therapeutic interest in the context of cancer. We recently developed the pure antagonist Del1-9-G129R-hPRL by deleting the nine N-terminal residues of G129R-hPRL, a first generation partial antagonist. We determined the crystallographic structure of Del1-9-G129R-hPRL, which revealed no major change compared with wild type hPRL, indicating that its pure antagonistic properties are intrinsically due to the mutations. To decipher the molecular bases of pure antagonism, we compared the biological, physicochemical, and structural properties of numerous hPRL variants harboring N-terminal or Gly(129) mutations, alone or combined. The pure versus partial antagonistic properties of the multiple hPRL variants could not be correlated to differences in their affinities toward the hPRL receptor, especially at site 2 as determined by surface plasmon resonance. On the contrary, residual agonism of the hPRL variants was found to be inversely correlated to their thermodynamic stability, which was altered by all the Gly(129) mutations but not by those involving the N terminus. We therefore propose that residual agonism can be abolished either by further disrupting hormone site 2-receptor contacts by N-terminal deletion, as in Del1-9-G129R-hPRL, or by stabilizing hPRL and constraining its intrinsic flexibility, as in G129V-hPRL. Udgivelsesdato: 2007-Nov-9
AB - Competitive antagonists of the human prolactin (hPRL) receptor are a novel class of molecules of potential therapeutic interest in the context of cancer. We recently developed the pure antagonist Del1-9-G129R-hPRL by deleting the nine N-terminal residues of G129R-hPRL, a first generation partial antagonist. We determined the crystallographic structure of Del1-9-G129R-hPRL, which revealed no major change compared with wild type hPRL, indicating that its pure antagonistic properties are intrinsically due to the mutations. To decipher the molecular bases of pure antagonism, we compared the biological, physicochemical, and structural properties of numerous hPRL variants harboring N-terminal or Gly(129) mutations, alone or combined. The pure versus partial antagonistic properties of the multiple hPRL variants could not be correlated to differences in their affinities toward the hPRL receptor, especially at site 2 as determined by surface plasmon resonance. On the contrary, residual agonism of the hPRL variants was found to be inversely correlated to their thermodynamic stability, which was altered by all the Gly(129) mutations but not by those involving the N terminus. We therefore propose that residual agonism can be abolished either by further disrupting hormone site 2-receptor contacts by N-terminal deletion, as in Del1-9-G129R-hPRL, or by stabilizing hPRL and constraining its intrinsic flexibility, as in G129V-hPRL. Udgivelsesdato: 2007-Nov-9
U2 - 10.1074/jbc.M704364200
DO - 10.1074/jbc.M704364200
M3 - Journal article
C2 - 17785459
VL - 282
SP - 33118
EP - 33131
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 45
ER -
ID: 2890645