PDBsum entry 1s2a

Oxidoreductase

PDB id: 1s2a

Contents

Protein chain

315 a.a. *

Ligands

NAP

IMN

DMS

UNX

Waters ×361

* Residue conservation analysis

PDB id:

1s2a

Name:

Oxidoreductase

Title:

Crystal structures of prostaglandin d2 11-ketoreductase in complex with the non-steroidal anti-inflammatory drugs flufenamic acid and indomethacin

Structure:

Aldo-keto reductase family 1 member c3. Chain: a. Synonym: akr1c3, prostaglandin d2 11-ketoreductase, prostaglandin f synthase, 3-alpha-hsd-type-2, 17-beta-hsd-type-5. Engineered: yes

Source:

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

Resolution:

1.70Å R-factor: 0.174 R-free: 0.198

Authors:

A.L.Lovering,J.P.Ride,C.M.Bunce,J.C.Desmond,S.M.Cummings,S.A.White

Key ref:

A.L.Lovering et al. (2004). Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res, 64, 1802-1810. PubMed id: 14996743 DOI: 10.1158/0008-5472.CAN-03-2847

Date:

08-Jan-04 Release date: 23-Mar-04

Protein chain

P42330  (AK1C3_HUMAN) -  Aldo-keto reductase family 1 member C3 from Homo sapiens

Seq: 323 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.188 - prostaglandin-F synthase.
• Reaction: prostaglandin F2alpha + NADP⁺ = prostaglandin D2 + NADPH + H⁺

prostaglandin F2alpha (Bound ligand (Het Group name = NAP) corresponds exactly) + NADP(+) = prostaglandin D2 + NADPH + H(+)

• Enzyme class 2: E.C.1.1.1.210 - 3beta-(or 20alpha)-hydroxysteroid dehydrogenase.
• Reaction: 5alpha-androstane-3beta,17beta-diol + NADP⁺ = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H⁺

5alpha-androstane-3beta,17beta-diol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 17beta-hydroxy-5alpha- androstan-3-one + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.239 - 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
• Reaction: testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺

testosterone (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+)

• Enzyme class 4: E.C.1.1.1.357 - 3alpha-hydroxysteroid 3-dehydrogenase.
• Reaction:
  1. a 3alpha-hydroxysteroid + NADP⁺ = a 3-oxosteroid + NADPH + H⁺
  2. a 3alpha-hydroxysteroid + NAD⁺ = a 3-oxosteroid + NADH + H⁺

3alpha-hydroxysteroid + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 3-oxosteroid + NADPH + H(+)

3alpha-hydroxysteroid + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 3-oxosteroid + NADH + H(+)

• Enzyme class 5: E.C.1.1.1.53 - 3alpha(or 20beta)-hydroxysteroid dehydrogenase.
• Reaction: androstan-3alpha,17beta-diol + NAD⁺ = 17beta-hydroxyandrostanone + NADH + H⁺

androstan-3alpha,17beta-diol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = 17beta-hydroxyandrostanone + NADH + H(+)

• Enzyme class 6: E.C.1.1.1.62 - 17beta-estradiol 17-dehydrogenase.
• Reaction:
  1. 17beta-estradiol + NAD⁺ = estrone + NADH + H⁺
  2. 17beta-estradiol + NADP⁺ = estrone + NADPH + H⁺

17beta-estradiol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = estrone + NADH + H(+)

17beta-estradiol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = estrone + NADPH + H(+)

• Enzyme class 7: E.C.1.1.1.64 - testosterone 17beta-dehydrogenase (NADP(+)).
• Reaction: testosterone + NADP⁺ = androst-4-ene-3,17-dione + NADPH + H⁺

testosterone (Bound ligand (Het Group name = NAP) corresponds exactly) + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

DOI no: 10.1158/0008-5472.CAN-03-2847

Cancer Res 64:1802-1810 (2004)

PubMed id: 14996743

Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.

A.L.Lovering, J.P.Ride, C.M.Bunce, J.C.Desmond, S.M.Cummings, S.A.White.

ABSTRACT

It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.