PDBsum entry 3jwr

Hydrolase

PDB id: 3jwr

Contents

Protein chains

323 a.a. *

17 a.a. *

Ligands

IBM ×5

Metals

_ZN ×2

_MG ×2

Waters ×17

* Residue conservation analysis

PDB id:

3jwr

Name:

Hydrolase

Title:

Crystal structure of chimeric pde5/pde6 catalytic domain complexed with 3-isobutyl-1-methylxanthine (ibmx) and pde6 gamma-subunit inhibitory peptide 70-87.

Structure:

Cgmp-specific 3',5'-cyclic phosphodiesterase catalytic domain, cone cgmp-specific 3',5'-cyclic phosphodiesterase subunit alpha chimera. Chain: a, b. Synonym: cgmp-binding cgmp-specific phosphodiesterase, cgb-pde, cgmp phosphodiesterase 6c. Engineered: yes. Retinal rod rhodopsin-sensitive cgmp 3',5'-cyclic phosphodiesterase subunit gamma.

Source:

Homo sapiens. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Human. Other_details: this sequence occurs naturally in humans.

Resolution:

2.99Å R-factor: 0.216 R-free: 0.280

Authors:

B.Barren,L.Gakhar,H.Muradov,K.K.Boyd,S.Ramaswamy,N.O.Artemyev

Key ref:

B.Barren et al. (2009). Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit. Embo J, 28, 3613-3622. PubMed id: 19798052

Date:

18-Sep-09 Release date: 13-Oct-09

Protein chains

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

Seq: 875 a.a.

Struc: 323 a.a.*

Protein chains

P51160  (PDE6C_HUMAN) -  Cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha' from Homo sapiens

Seq: 858 a.a.

Struc: 323 a.a.*

Protein chains

P18545  (CNRG_HUMAN) -  Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma from Homo sapiens

Seq: 87 a.a.

Struc: 17 a.a.

* PDB and UniProt seqs differ at 188 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: 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

Embo J 28:3613-3622 (2009)

PubMed id: 19798052

Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit.

B.Barren, L.Gakhar, H.Muradov, K.K.Boyd, S.Ramaswamy, N.O.Artemyev.

ABSTRACT

The inhibitory interaction of phosphodiesterase-6 (PDE6) with its gamma-subunit (Pgamma) is pivotal in vertebrate phototransduction. Here, crystal structures of a chimaeric PDE5/PDE6 catalytic domain (PDE5/6cd) complexed with sildenafil or 3-isobutyl-1-methylxanthine and the Pgamma-inhibitory peptide Pgamma(70-87) have been determined at 2.9 and 3.0 A, respectively. These structures show the determinants and the mechanism of the PDE6 inhibition by Pgamma and suggest the conformational change of Pgamma on transducin activation. Two variable H- and M-loops of PDE5/6cd form a distinct interface that contributes to the Pgamma-binding site. This allows the Pgamma C-terminus to fit into the opening of the catalytic pocket, blocking cGMP access to the active site. Our analysis suggests that disruption of the H-M loop interface and Pgamma-binding site is a molecular cause of retinal degeneration in atrd3 mice. Comparison of the two PDE5/6cd structures shows an overlap between the sildenafil and Pgamma(70-87)-binding sites, thereby providing critical insights into the side effects of PDE5 inhibitors on vision.