2Q98

X-ray structure of a prolactin antagonist

2Q98 の概要

• エントリーDOI: 10.2210/pdb2q98/pdb
• 分子名称: Prolactin (2 entities in total)
• 機能のキーワード: antagonist receptor interaction, hormone
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P01236
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22364.52

構造登録者

Broutin, I.J.L.,Ducruix, A.,Jomain, J.B.,Goffin, V. (登録日: 2007-06-12, 公開日: 2007-09-11, 最終更新日: 2024-11-13)

主引用文献

Jomain, J.B.,Tallet, E.,Broutin, I.,Hoos, S.,van Agthoven, J.,Ducruix, A.,Kelly, P.A.,Kragelund, B.B.,England, P.,Goffin, V.
Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL.
J.Biol.Chem., 282:33118-33131, 2007

PubMed Abstract: 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.

PubMed: 17785459
DOI: 10.1074/jbc.M704364200

実験手法

X-RAY DIFFRACTION (2.7 Å)