3U4H

CD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose template

3U4H の概要

• エントリーDOI: 10.2210/pdb3u4h/pdb
• 関連するPDBエントリー: 3U4I
• 分子名称: ADP-ribosyl cyclase 1, 8-Amino-N1-Cyclic Inosine 5'-Diphosphoribose (3 entities in total)
• 機能のキーワード: non-hydrolyzable inhibitor, two domains, cadpr cyclization, hydrolysis, 8-amino-n1-cidpr, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type II membrane protein: P28907
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61875.39

構造登録者

Liu, Q.,Hao, Q.,Lee, H.C.,Graeff, R. (登録日: 2011-10-08, 公開日: 2012-10-10, 最終更新日: 2024-10-30)

主引用文献

Moreau, C.,Liu, Q.,Graeff, R.,Wagner, G.K.,Thomas, M.P.,Swarbrick, J.M.,Shuto, S.,Lee, H.C.,Hao, Q.,Potter, B.V.L.
CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template
Plos One, 8:e66247-e66247, 2013

PubMed Abstract: Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca(2+)-mobilizing second messenger cyclic adenosine 5'-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5'-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR "northern" ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5'-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design.

PubMed: 23840430
DOI: 10.1371/journal.pone.0066247

実験手法

X-RAY DIFFRACTION (1.878 Å)