PDBsum entry: 1xlz

Hydrolase

PDB-id: 1xlz

Biological unit* = asymmetric unit, as shown
(*as deduced by PQS)

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Description

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Header records

References

PROCHECK

Protein chains

323 a.a. *

Ligands

FIL ×2

Metal ions

_ZN ×2

_MG ×2

Waters ×152

* Residue conservation analysis

Tools

Clefts Calculation

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PDB id:

1xlz

Name:

Hydrolase

Title:

Catalytic domain of human phosphodiesterase 4b in complex with filaminast

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a, b. Fragment: catalytic domain of human phosphodiesterase 4b. Synonym: dpde4, pde32. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde4b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biological unit:

Dimer (from PQS)

UniProt:

Chains A, B: Q07343 (PDE4B_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

736 a.a.

Struc:

323 a.a.*

Key:	PfamA domain
Secondary structure	CATH domain

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

Enzyme class:

E.C.3.1.4.17   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

Nucleoside 3',5'-cyclic phosphate + H₂O = nucleoside 5'-phosphate (see diagram below)

Resolution:

2.06Å

R-factor:

0.210

R-free:

0.237

Authors:

G.L.Card,B.P.England,Y.Suzuki,D.Fong,B.Powell,B.Lee,C.Luu, M.Tabrizizad,S.Gillette,P.N.Ibrahim,D.R.Artis,G.Bollag, M.V.Milburn,S.-H.Kim,J.Schlessinger,K.Y.J.Zhang

Key ref:

G.L.Card et al. (2004). Structural basis for the activity of drugs that inhibit phosphodiesterases.. Structure, 12, 2233-2247. [PubMed id: 15576036] [DOI: 10.1016/j.str.2004.10.004]

Date:

30-Sep-04

Release date:

14-Dec-04

Related entries:

1xlx
pde4b in complex with cilomilast
1xm4
pde4b in complex with piclamilast
1xm6
pde4b in complex with (r)-mesopram
1xmu
pde4b in complex with roflumilast
1xmy
pde4b in complex with (r)-rolipram
... plus others (see Header records)

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Clefts

Surface

Key reference

DOI no: 10.1016/j.str.2004.10.004

Structure 12:2233-2247 (2004)

PubMed id: 15576036

Structural basis for the activity of drugs that inhibit phosphodiesterases.

G.L.Card, B.P.England, Y.Suzuki, D.Fong, B.Powell, B.Lee, C.Luu, M.Tabrizizad, S.Gillette, P.N.Ibrahim, D.R.Artis, G.Bollag, M.V.Milburn, S.H.Kim, J.Schlessinger, K.Y.Zhang.

ABSTRACT

Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.

Selected figure(s)

Figure 1.
Figure 1. Classification of the Active Site of PDEs(A) The active site of PDEs is divided into three pockets: the metal binding pocket (M) shown in blue, the purine-selective glutamine and hydrophobic clamp pocket (Q) shown in red (which is further divided into Q[1] and Q[2] subpockets), and the solvent-filled side pocket (S) shown in green. This color coding of the active site pocket is mapped on the surface of PDE4B in complex with cilomilast, which is shown as a stick model bound at the active site. The cocrystal structure of PDE4B in complex with cilomilast has also been used to display the surfaces in (B)-(D).(B) Same as (A), but a view of the PDE active site looking toward the S pocket. This view is a clockwise rotation of about 90° along the length of cilomilast from the view in Figure 1A. The subpockets that subdivide the Q pocket are also labeled: Q[1] is the small subpocket, and Q[2] is the large subpocket.(C) Same as (A), but a view of the PDE active site looking away from the S pocket. This view is a counterclockwise rotation of about 90° along the length of cilomilast from the view in Figure 1A. All the subpockets are labeled.(D) Residues lining the three active site pockets. The active site surface is semitransparent to reveal residues that make up the active site. The absolutely conserved residues in all PDEs are colored blue. Residues conserved in both cAMP- and cGMP-specific PDEs are colored green. The other variable residues are colored red.

The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 2233-2247) copyright 2004.

Figure was selected by the author.