3U4I

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

Summary for 3U4I

• Entry DOI: 10.2210/pdb3u4i/pdb
• Related: 3U4H
• Descriptor: ADP-ribosyl cyclase 1, Cyclic adenosine 5'-diphosphocarbocyclic ribose (3 entities in total)
• Functional Keywords: non-hydrolyzable inhibitor, two domains, cadpr cyclization, hydrolysis, cadpcr, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type II membrane protein: P28907
• Total number of polymer chains: 2
• Total formula weight: 61300.11

Authors

Liu, Q.,Hao, Q.,Lee, H.C.,Graeff, R. (deposition date: 2011-10-08, release date: 2012-10-10, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.118 Å)