4HTZ

Crystal structure of PDE2 catalytic domain in space group P1

Summary for 4HTZ

• Entry DOI: 10.2210/pdb4htz/pdb
• Related: 4HTX
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• Total number of polymer chains: 4
• Total formula weight: 160221.96

Authors

Zhu, J.,Huang, Q. (deposition date: 2012-11-02, release date: 2013-08-28, Last modification date: 2024-02-28)

Primary citation

Zhu, J.,Yang, Q.,Dai, D.,Huang, Q.
X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity.
J.Am.Chem.Soc., 135:11708-11711, 2013

PubMed Abstract: To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the structure of apo PDE2 at 2.0 Å resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.

PubMed: 23899287
DOI: 10.1021/ja404449g

Experimental method

X-RAY DIFFRACTION (2 Å)