4EBB

Structure of DPP2

4EBB の概要

• エントリーDOI: 10.2210/pdb4ebb/pdb
• 関連するPDBエントリー: 3JYH
• 分子名称: Dipeptidyl peptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (4 entities in total)
• 機能のキーワード: peptidase, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Lysosome: Q9UHL4
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106544.37

構造登録者

Shewchuk, L.M.,Hassell, A.H.,Sweitzer, S.M.,Sweitzer, T.D.,McDevitt, P.J.,Kennedy-Wilson, K.M.,Johanson, K.O. (登録日: 2012-03-23, 公開日: 2012-09-19, 最終更新日: 2024-10-16)

主引用文献

Bezerra, G.A.,Dobrovetsky, E.,Dong, A.,Seitova, A.,Crombett, L.,Shewchuk, L.M.,Hassell, A.M.,Sweitzer, S.M.,Sweitzer, T.D.,McDevitt, P.J.,Johanson, K.O.,Kennedy-Wilson, K.M.,Cossar, D.,Bochkarev, A.,Gruber, K.,Dhe-Paganon, S.
Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases.
Plos One, 7:e43019-e43019, 2012

PubMed Abstract: Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/β-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The "specificity domains" are structurally also completely different exhibiting a β-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.

PubMed: 22952628
DOI: 10.1371/journal.pone.0043019

実験手法

X-RAY DIFFRACTION (2 Å)