PDBsum entry 3gwt

Hydrolase

PDB id

3gwt

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Contents

			Protein chain

					336 a.a. *

			Ligands

					066


					ARS ×4


					GOL ×3

			Metals

					_ZN


					_MG

			Waters ×321

* Residue conservation analysis

PDB id:

3gwt

Links

Name:

Hydrolase

Title:

Catalytic domain of human phosphodiesterase 4b2b in complex with a quinoline inhibitor

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a. Fragment: catalytic domain, residues 324-675. Synonym: dpde4, pde32. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4b, dpde4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.75Å

R-factor:

0.207

R-free:

0.250

Authors:

D.O.Somers,M.Neu

Key ref:

M.D.Woodrow et al. (2009). Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration. Bioorg Med Chem Lett, 19, 5261-5265. PubMed id: 19656678

Date:

01-Apr-09

Release date:

07-Apr-10

PROCHECK

	Headers

	References

Protein chain

Q07343 (PDE4B_HUMAN) - cAMP-specific 3',5'-cyclic phosphodiesterase 4B from Homo sapiens

Seq: Struc:

Seq: Struc:					736 a.a. 336 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

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



		Enzyme reactions

Enzyme class:

E.C.3.1.4.53 - 3',5'-cyclic-AMP phosphodiesterase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

3',5'-cyclic AMP + H2O = AMP + H⁺

3',5'-cyclic AMP	+	H2O	=	AMP	+	H(+)

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

Added reference

	Bioorg Med Chem Lett 19:5261-5265 (2009)
PubMed id: 19656678

Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration.
M.D.Woodrow, S.P.Ballantine, M.D.Barker, B.J.Clarke, J.Dawson, T.W.Dean, C.J.Delves, B.Evans, S.L.Gough, S.B.Guntrip, S.Holman, D.S.Holmes, M.Kranz, M.K.Lindvaal, F.S.Lucas, M.Neu, L.E.Ranshaw, Y.E.Solanke, D.O.Somers, P.Ward, J.O.Wiseman.

ABSTRACT

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20673774

R.E.Hubbard (2011).
Structure-based drug discovery and protein targets in the CNS.

Neuropharmacology, 60, 7.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.