8A7D

Partial dimer complex of PAPP-A and its inhibitor STC2

8A7D の概要

• エントリーDOI: 10.2210/pdb8a7d/pdb
• EMDBエントリー: 15220
• 分子名称: Pappalysin-1, Stanniocalcin-2, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: metzincin metalloprotease inhibitor complex, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 363261.60

構造登録者

Kobbero, S.D.,Gajhede, M.,Mirza, O.A.,Boesen, T.,Oxvig, C. (登録日: 2022-06-20, 公開日: 2022-11-02, 最終更新日: 2024-11-20)

主引用文献

Kobbero, S.D.,Gajhede, M.,Mirza, O.A.,Kloverpris, S.,Kjaer, T.R.,Mikkelsen, J.H.,Boesen, T.,Oxvig, C.
Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism.
Nat Commun, 13:6084-6084, 2022

PubMed Abstract: The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated.

PubMed: 36257932
DOI: 10.1038/s41467-022-33698-8

実験手法

ELECTRON MICROSCOPY (3.06 Å)