PDBsum entry 2zb4

Oxidoreductase

PDB id: 2zb4

Contents

Protein chain

351 a.a. *

Ligands

SO4 ×4

NAP

5OP

Waters ×618

* Residue conservation analysis

PDB id:

2zb4

Name:

Oxidoreductase

Title:

Crystal structure of human 15-ketoprostaglandin delta-13-reductase in complex with NADP and 15-keto-pge2

Structure:

Prostaglandin reductase 2. Chain: a. Synonym: ptgr2, 15-oxoprostaglandin 13-reductase, zinc-binding alcohol dehydrogenase domain-containing protein 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptgr2, zadh1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.63Å R-factor: 0.184 R-free: 0.244

Authors:

Y.H.Wu,A.H.J.Wang,T.P.Ko,R.T.Guo,S.M.Hu,L.M.Chuang

Key ref:

Y.H.Wu et al. (2008). Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2. Structure, 16, 1714-1723. PubMed id: 19000823 DOI: 10.1016/j.str.2008.09.007

Date:

16-Oct-07 Release date: 30-Sep-08

Protein chain

Q8N8N7  (PTGR2_HUMAN) -  Prostaglandin reductase 2 from Homo sapiens

Seq: 351 a.a.

Struc: 351 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.1.48 - 15-oxoprostaglandin 13-reductase.
• Reaction:
  1. 13,14-dihydro-15-oxo-prostaglandin E2 + NADP⁺ = 15-oxoprostaglandin E2 + NADPH + H⁺
  2. 13,14-dihydro-15-oxo-prostaglandin E2 + NAD⁺ = 15-oxoprostaglandin E2 + NADH + H⁺

13,14-dihydro-15-oxo-prostaglandin E2 + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 15-oxoprostaglandin E2 + NADPH + H(+)

13,14-dihydro-15-oxo-prostaglandin E2 + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 15-oxoprostaglandin E2 + NADH + H(+)

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

reference

DOI no: 10.1016/j.str.2008.09.007

Structure 16:1714-1723 (2008)

PubMed id: 19000823

Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2.

Y.H.Wu, T.P.Ko, R.T.Guo, S.M.Hu, L.M.Chuang, A.H.Wang.

ABSTRACT

PTGR2 catalyzes an NADPH-dependent reduction of the conjugated alpha,beta-unsaturated double bond of 15-keto-PGE(2), a key step in terminal inactivation of prostaglandins and suppression of PPARgamma-mediated adipocyte differentiation. Selective inhibition of PTGR2 may contribute to the improvement of insulin sensitivity with fewer side effects. PTGR2 belongs to the medium-chain dehydrogenase/reductase superfamily. The crystal structures reported here reveal features of the NADPH binding-induced conformational change in a LID motif and a polyproline type II helix which are critical for the reaction. Mutation of Tyr64 and Tyr259 significantly reduces the rate of catalysis but increases the affinity to substrate, confirming the structural observations. Besides targeting cyclooxygenase, indomethacin also inhibits PTGR2 with a binding mode similar to that of 15-keto-PGE(2). The LID motif becomes highly disordered upon the binding of indomethacin, indicating plasticity of the active site. This study has implications for the rational design of inhibitors of PTGR2.

Selected figure(s)

Figure 2.
Figure 2. Structure-Based Sequence Alignment of PTGR2 and Homologs
(A) Stereo view of the crystal structure of the hPTGR2-NADP^+-15-keto-PGE[2] complex. The nucleotide-binding domain (H149–Y292) and catalytic domain (M1-G148; K293–L351) are colored in purple and orange, respectively. The NADP^+ (yellow carbons), 15-keto-PGE[2] (green carbons), and sulfate ions (dark yellow sulfurs) are shown as ball-and-stick models.
(B) Multiple sequence alignments of human PTGR2 (SwissProt entry Q8N8N7), mouse PTGR2 (Q3TG36), guinea pig 13-PGR/LTB[4]DH (Q9EQZ5), and human 13-PGR/LTB[4]DH (A8K0N2). The LID motifs and PPII helices of PTGR2 are indicated by double-headed arrows. The conserved nucleotide-binding motif is underlined. Tyr64 and Tyr259 are marked with red boxes.

Figure 6.
Figure 6. Putative Catalytic Residues
Alignment of the active sites of hPTGR2 (cyan), mPTGR2 (magenta), 13-PGR/LTB[4]DH (yellow), and Etr1p (gray). Hydrogen bonds in PTGR2 and Etr1p are in red and blue, respectively. Tyr262(B) is from the countersubunit B of 13-PGR/LTB[4]DH.

The above figures are reprinted by permission from Cell Press: Structure (2008, 16, 1714-1723) copyright 2008.

Figures were selected by an automated process.