PDBsum entry 1rkp

Hydrolase

PDB id: 1rkp

Contents

Protein chain

311 a.a. *

Ligands

IBM

Metals

_ZN

_MG

Waters ×133

* Residue conservation analysis

PDB id:

1rkp

Name:

Hydrolase

Title:

Crystal structure of pde5a1-ibmx

Structure:

Cgmp-specific 3',5'-cyclic phosphodiesterase. Chain: a. Fragment: catalytic domain (residues 535-860). Synonym: cgb-pde, cgmp-binding cgmp-specific phosphodiesterase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde5a, pde5, pde5a1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.05Å R-factor: 0.220 R-free: 0.243

Authors:

Q.Huai,Y.Liu,S.H.Francis,J.D.Corbin,H.Ke

Key ref:

Q.Huai et al. (2004). Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J Biol Chem, 279, 13095-13101. PubMed id: 14668322 DOI: 10.1074/jbc.M311556200

Date:

22-Nov-03 Release date: 30-Mar-04

Protein chain

O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 875 a.a.

Struc: 311 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺

3',5'-cyclic GMP (Bound ligand (Het Group name = IBM) matches with 50.00% similarity) + H2O = GMP + H(+)

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

Added reference

DOI no: 10.1074/jbc.M311556200

J Biol Chem 279:13095-13101 (2004)

PubMed id: 14668322

Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity.

Q.Huai, Y.Liu, S.H.Francis, J.D.Corbin, H.Ke.

ABSTRACT

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. Crystal structures of the catalytic domains of cGMP-specific PDE5A1 and cAMP-specific PDE4D2 in complex with the nonselective inhibitor 3-isobutyl-1-methylxanthine have been determined at medium resolution. The catalytic domain of PDE5A1 has the same topological folding as that of PDE4D2, but three regions show different tertiary structures, including residues 79-113, 208-224 (H-loop), and 341-364 (M-loop) in PDE4D2 or 535-566, 661-676, and 787-812 in PDE5A1, respectively. Because H- and M-loops are involved in binding of the selective inhibitors, the different conformations of the loops, thus the distinct shapes of the active sites, will be a determinant of inhibitor selectivity in PDEs. IBMX binds to a subpocket that comprises key residues Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817, and Phe-820 of PDE5A1. This subpocket may be a common site for binding nonselective inhibitors of PDEs.

Selected figure(s)

Figure 1.
FIG. 1. Structures of the PDE-IBMX complexes. A, ribbon diagram of PDE4D2-IBMX. The -helices are colored as cyan, and blue color represents 3[10] helices. The first metal ion is interpreted as zinc, as discussed previously (31, 33), whereas the second metal ion (Me2) is ambiguous. B, ribbon diagram of PDE5A1-IBMX. The second metal ion was assigned as magnesium because 0.2 M MgSO[4] was used in the crystallization buffer. C, the structural superposition between PDE4D2 and PDE5A1. The cyan ribbons represent the conserved core structures between PDE4D2 and PDE5A1. The variable regions are drawn in gold for PDE4D2 and green for PDE5A1. D, the correspondence of amino acid sequence to the secondary structures.

Figure 2.
FIG. 2. IBMX binding. Stereoview of the electron density for IBMX bound to PDE4D2 (A) and PDE5A1 (B). The 2F[o] - F[c] maps were calculated from the structures omitted IBMX and contoured at 1.5 for PDE4D2 and 2.0 for PDE5A1. C, chemical structure of IBMX. D, IBMX binding to the active site of PDE4D2. The xanthine group stacks against Phe-372 and forms hydrogen bond with Gln-369 (dotted lines). E, IBMX binding to the active site of PDE5A1.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 13095-13101) copyright 2004.