PDBsum entry 4htx

Hydrolase/hydrolase inhibitor

PDB id: 4htx

Contents

Protein chain

338 a.a.

Ligands

19F ×4

Metals

_ZN ×4

_MG ×4

Waters ×705

PDB id:

4htx

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pde2 catalytic domain in complex with bay60-7550

Structure:

Cgmp-dependent 3',5'-cyclic phosphodiesterase. Chain: a, b, c, d. Fragment: catalytic domain, unp residues 578-919. Synonym: cyclic gmp-stimulated phosphodiesterase, cgs-pde, cgspde. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde2a. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.175 R-free: 0.227

Authors:

J.Zhu,Q.Huang

Key ref:

J.Zhu et al. (2013). 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. PubMed id: 23899287 DOI: 10.1021/ja404449g

Date:

02-Nov-12 Release date: 28-Aug-13

Protein chains

O00408  (PDE2A_HUMAN) -  cGMP-dependent 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 941 a.a.

Struc: 338 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.17 - 3',5'-cyclic-nucleotide phosphodiesterase.
• Reaction: a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/ja404449g

J Am Chem Soc 135:11708-11711 (2013)

PubMed id: 23899287

X-ray crystal structure of phosphodiesterase 2 in complex with a highly selective, nanomolar inhibitor reveals a binding-induced pocket important for selectivity.

J.Zhu, Q.Yang, D.Dai, Q.Huang.

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.