6VGR

Crystal Structure of Human Dipeptidase 3 in Complex with Fab of SC-003

6VGR の概要

• エントリーDOI: 10.2210/pdb6vgr/pdb
• 分子名称: Dipeptidase 3, SC-003 Fab Heavy Chain, SC-003 Fab Light Chain, ... (4 entities in total)
• 機能のキーワード: fab, antibody drug conjugate, dipeptidase, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 203286.86

構造登録者

Hayashi, K.,Longenecker, K.L.,Vivona, S. (登録日: 2020-01-08, 公開日: 2020-05-13, 最終更新日: 2024-10-30)

主引用文献

Hayashi, K.,Longenecker, K.L.,Koenig, P.,Prashar, A.,Hampl, J.,Stoll, V.,Vivona, S.
Structure of human DPEP3 in complex with the SC-003 antibody Fab fragment reveals basis for lack of dipeptidase activity.
J.Struct.Biol., 211:107512-107512, 2020

PubMed Abstract: Dipeptidase 3 (DPEP3) is one of three glycosylphosphatidylinositol-anchored metallopeptidases potentially involved in the hydrolytic metabolism of dipeptides. While its exact biological function is not clear, DPEP3 expression is normally limited to testis, but can be elevated in ovarian cancer. Antibody drug conjugates targeting DPEP3 have shown efficacy in preclinical models with a pyrrolobenzodiazepine conjugate, SC-003, dosed in a phase I clinical trial (NCT02539719). Here we reveal the novel atomic structure of DPEP3 alone and in complex with the SC-003 Fab fragment at 1.8 and 2.8 Å, respectively. The structure of DPEP3/SC-003 Fab complex reveals an eighteen-residue epitope across the DPEP3 dimerization interface distinct from the enzymatic active site. DPEP1 and DPEP3 extracellular domains share a conserved, dimeric TIM (β/α)8-barrel fold, consistent with 49% sequence identity. However, DPEP3 diverges from DPEP1 and DPEP2 in key positions of its active site: a histidine to tyrosine variation at position 269 reduces affinity for the β zinc and may cause substrate steric hindrance, whereas an aspartate to asparagine change at position 359 abolishes activation of the nucleophilic water/hydroxide, resulting in no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine). Hence DPEP3, unlike DPEP1 and DPEP2, may require an activating co-factor in vivo or may remain an inactive, degenerate enzyme. This report sheds light on the structural discriminants between active and inactive membrane dipeptidases and provides a benchmark to characterize current and future DPEP3-targeted therapeutic approaches.

PubMed: 32325220
DOI: 10.1016/j.jsb.2020.107512

実験手法

X-RAY DIFFRACTION (2.84 Å)