5EHH

Structure of human DPP3 in complex with endomorphin-2.

5EHH の概要

• エントリーDOI: 10.2210/pdb5ehh/pdb
• 関連するPDBエントリー: 3FVY 3T6B
• 分子名称: Dipeptidyl peptidase 3, Endomorphin-2, ZINC ION, ... (6 entities in total)
• 機能のキーワード: inhibitor-complex, peptidase, zinc-hydrolase, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm, cytosol : Q9NY33
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82272.46

構造登録者

Kumar, P.,Reithofer, V.,Reisinger, M.,Pavkov-Keller, T.,Wallner, S.,Macheroux, P.,Gruber, K. (登録日: 2015-10-28, 公開日: 2016-04-13, 最終更新日: 2024-11-13)

主引用文献

Kumar, P.,Reithofer, V.,Reisinger, M.,Wallner, S.,Pavkov-Keller, T.,Macheroux, P.,Gruber, K.
Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.
Sci Rep, 6:23787-23787, 2016

PubMed Abstract: Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or "slow" substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.

PubMed: 27025154
DOI: 10.1038/srep23787

実験手法

X-RAY DIFFRACTION (2.38 Å)