PDBsum entry 4zo5

Hydrolase/hydrolase inhibitor

PDB id: 4zo5

Contents

Protein chains

323 a.a.

Ligands

4PX

4Q0

Metals

_ZN ×2

_MG ×2

Waters ×22

PDB id:

4zo5

Name:

Hydrolase/hydrolase inhibitor

Title:

Pde10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-2-yl)ethyl)isoindoline-1,3-dione

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain, unp residues 449-769. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.50Å R-factor: 0.241 R-free: 0.285

Authors:

Y.Yan

Key ref:

C.D.Cox et al. (2015). Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett, 25, 4893-4898. PubMed id: 26077491 DOI: 10.1016/j.bmcl.2015.05.080

Date:

06-May-15 Release date: 12-Aug-15

Protein chains

Q9Y233  (PDE10_HUMAN) -  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A from Homo sapiens

Seq: 779 a.a.

Struc: 323 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1016/j.bmcl.2015.05.080

Bioorg Med Chem Lett 25:4893-4898 (2015)

PubMed id: 26077491

Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.

C.D.Cox, E.D.Hostetler, B.A.Flores, J.L.Evelhoch, H.Fan, L.Gantert, M.Holahan, W.Eng, A.Joshi, G.McGaughey, X.Meng, M.Purcell, I.T.Raheem, K.Riffel, Y.Yan, J.J.Renger, S.M.Smith, P.J.Coleman.

ABSTRACT

Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.