PDBsum entry 3r8h

Oxidoreductase/oxidoreductase inhibitor

PDB id: 3r8h

Contents

Protein chain

303 a.a.

Ligands

NAP

ZOM

EDO ×2

Waters ×123

PDB id:

3r8h

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Akr1c3 complex with zomepirac

Structure:

Aldo-keto reductase family 1 member c3. Chain: a. Synonym: 17-beta-hydroxysteroid dehydrogenase type 5, 17-beta-hsd 5, 3-alpha-hsd type ii, brain, 3-alpha-hydroxysteroid dehydrogenase type 2, 3-alpha-hsd type 2, chlordecone reductase homolog hakrb, dihydrodiol dehydrogenase 3, dd-3, dd3, dihydrodiol dehydrogenase type i, ha1753, indanol dehydrogenase, prostaglandin f synthase, pgfs, testosterone 17-beta-dehydrogenase 5, trans-1,2-dihydrobenzene- 1,2-diol dehydrogenase.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1c3, ddh1, hsd17b5, kiaa0119, pgfs. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.90Å R-factor: 0.166 R-free: 0.204

Authors:

Y.Yosaatmadja,R.M.Teague,J.U.Flanagan,C.J.Squire

Key ref:

J.U.Flanagan et al. (2012). Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3. Plos One, 7, e43965. PubMed id: 22937138

Date:

24-Mar-11 Release date: 02-May-12

Protein chain

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

Seq: 323 a.a.

Struc: 303 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(+) (Bound ligand (Het Group name = ZOM) matches with 50.00% similarity) = 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 (Bound ligand (Het Group name = ZOM) matches with 57.69% similarity) + 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(+) (Bound ligand (Het Group name = ZOM) matches with 57.69% similarity) = 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 (Bound ligand (Het Group name = ZOM) matches with 60.00% similarity) + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = 3-oxosteroid + NADPH + H(+)

3alpha-hydroxysteroid (Bound ligand (Het Group name = ZOM) matches with 60.00% similarity) + 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 (Bound ligand (Het Group name = ZOM) matches with 57.69% similarity) + 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 (Bound ligand (Het Group name = ZOM) matches with 60.00% similarity) + NADH + H(+)

17beta-estradiol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = estrone (Bound ligand (Het Group name = ZOM) matches with 60.00% similarity) + 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(+) (Bound ligand (Het Group name = ZOM) matches with 57.69% similarity) = 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

Plos One 7:e43965 (2012)

PubMed id: 22937138

Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3.

J.U.Flanagan, Y.Yosaatmadja, R.M.Teague, M.Z.Chai, A.P.Turnbull, C.J.Squire.

ABSTRACT

Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts.