Structure of PDB 4h7c Chain A Binding Site BS01

Receptor Information

>4h7c Chain A (length=306) Species: 9606 (Homo sapiens)

HQCVKLNDGHFMPVLGFGTYAPPEVPRSKALEVTKLAIEAGFRHIDSAHL
YNNEEQVGLAIRSKIADGSVKREDIFYTSKLWSTFHRPELVRPALENSLK
KAQLDYVDLYLIHSPMSLKPGEIFDIVDLCTTWEAMEKCKDAGLAKSIGV
SNFNRRQLEMILNKPGLKYKPVCNQVECHPYFNRSKLLDFCKSKDIVLVA
YSALGSQRDKRWVDPNSPVLLEDPVLCALAKKHKRTPALIALRYQLQRGV
VVLAKSYNEQRIRQNVQVFEFQLTAEDMKAIDGLDRNLHYFNSDSFASHP
NYPYSD

Ligand information

• Ligand ID: NAP
• InChI: InChI=1S/C21H28N7O17P3/c22-17-12-19(25-7-24-17)28(8-26-12)21-16(44-46(33,34)35)14(30)11(43-21)6-41-48(38,39)45-47(36,37)40-5-10-13(29)15(31)20(42-10)27-3-1-2-9(4-27)18(23)32/h1-4,7-8,10-11,13-16,20-21,29-31H,5-6H2,(H7-,22,23,24,25,32,33,34,35,36,37,38,39)/t10-,11-,13-,14-,15-,16-,20-,21-/m1/s1
• InChIKey: XJLXINKUBYWONI-NNYOXOHSSA-N
• SMILES:
  OpenEye OEToolkits 1.5.0: c1cc(c[n+](c1)C2C(C(C(O2)COP(=O)([O-])OP(=O)(O)OCC3C(C(C(O3)n4cnc5c4ncnc5N)OP(=O)(O)O)O)O)O)C(=O)N
  CACTVS 3.341: NC(=O)c1ccc[n+](c1)[CH]2O[CH](CO[P]([O-])(=O)O[P](O)(=O)OC[CH]3O[CH]([CH](O[P](O)(O)=O)[CH]3O)n4cnc5c(N)ncnc45)[CH](O)[CH]2O
  CACTVS 3.341: NC(=O)c1ccc[n+](c1)[C@@H]2O[C@H](CO[P]([O-])(=O)O[P@@](O)(=O)OC[C@H]3O[C@H]([C@H](O[P](O)(O)=O)[C@@H]3O)n4cnc5c(N)ncnc45)[C@@H](O)[C@H]2O
  OpenEye OEToolkits 1.5.0: c1cc(c[n+](c1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO[P@@](=O)([O-])O[P@](=O)(O)OC[C@@H]3[C@H]([C@H]([C@@H](O3)n4cnc5c4ncnc5N)OP(=O)(O)O)O)O)O)C(=O)N
• Formula: C21 H28 N7 O17 P3
• Name: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE;
  2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE
• ChEMBL: CHEMBL295069
• DrugBank: DB03461
• PDB chain: 4h7c Chain A Residue 401

Receptor-Ligand Complex Structure

Structure summary

• PDB: 4h7c Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3.
• Resolution: 1.97 Å
• Binding residue (original residue number in PDB): G22 T23 Y24 D50 Y55 H117 N167 Q190 Y216 S217 L219 S221 Q222 L236 A253 L268 K270 S271 R276 Q279 N280
• Binding residue (residue number reindexed from 1): G18 T19 Y20 D46 Y51 H113 N152 Q175 Y201 S202 L204 S206 Q207 L221 A238 L253 K255 S256 R261 Q264 N265
• Annotation score: 4

Enzymatic activity

• Catalytic site (original residue number in PDB): D50 Y55 K84 H117
• Catalytic site (residue number reindexed from 1): D46 Y51 K80 H113
• Enzyme Commision number: 1.1.1.-
  1.1.1.188: prostaglandin-F synthase.
  1.1.1.210: 3beta-(or 20alpha)-hydroxysteroid dehydrogenase.
  1.1.1.239: 3alpha-(17beta)-hydroxysteroid dehydrogenase (NAD(+)).
  1.1.1.357: 3alpha-hydroxysteroid 3-dehydrogenase.
  1.1.1.53: 3alpha(or 20beta)-hydroxysteroid dehydrogenase.
  1.1.1.62: 17beta-estradiol 17-dehydrogenase.
  1.1.1.64: testosterone 17beta-dehydrogenase (NADP(+)).

Gene Ontology

Molecular Function

• GO:0001758 retinal dehydrogenase activity
• GO:0004032 aldose reductase (NADPH) activity
• GO:0004033 aldo-keto reductase (NADPH) activity
• GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity
• GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity
• GO:0005515 protein binding
• GO:0016491 oxidoreductase activity
• GO:0016655 oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor
• GO:0032052 bile acid binding
• GO:0036130 prostaglandin H2 endoperoxidase reductase activity
• GO:0036131 prostaglandin D2 11-ketoreductase activity
• GO:0045550 geranylgeranyl reductase activity
• GO:0045703 ketoreductase activity
• GO:0047017 prostaglandin F synthase activity
• GO:0047020 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity
• GO:0047023 androsterone dehydrogenase activity
• GO:0047024 5alpha-androstane-3beta,17beta-diol dehydrogenase activity
• GO:0047035 testosterone dehydrogenase (NAD+) activity
• GO:0047044 androstan-3-alpha,17-beta-diol dehydrogenase activity
• GO:0047045 testosterone 17-beta-dehydrogenase (NADP+) activity
• GO:0047086 ketosteroid monooxygenase activity
• GO:0047787 Delta4-3-oxosteroid 5beta-reductase activity
• GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity

Biological Process

• GO:0001523 retinoid metabolic process
• GO:0006629 lipid metabolic process
• GO:0006693 prostaglandin metabolic process
• GO:0007186 G protein-coupled receptor signaling pathway
• GO:0007584 response to nutrient
• GO:0008202 steroid metabolic process
• GO:0008284 positive regulation of cell population proliferation
• GO:0008584 male gonad development
• GO:0009267 cellular response to starvation
• GO:0016488 farnesol catabolic process
• GO:0019371 cyclooxygenase pathway
• GO:0030216 keratinocyte differentiation
• GO:0042448 progesterone metabolic process
• GO:0042572 retinol metabolic process
• GO:0042574 retinal metabolic process
• GO:0043170 macromolecule metabolic process
• GO:0044597 daunorubicin metabolic process
• GO:0044598 doxorubicin metabolic process
• GO:0048385 regulation of retinoic acid receptor signaling pathway
• GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:0061370 testosterone biosynthetic process
• GO:0070293 renal absorption
• GO:0071277 cellular response to calcium ion
• GO:0071379 cellular response to prostaglandin stimulus
• GO:0071384 cellular response to corticosteroid stimulus
• GO:0071395 cellular response to jasmonic acid stimulus
• GO:0071799 cellular response to prostaglandin D stimulus
• GO:1900053 negative regulation of retinoic acid biosynthetic process
• GO:2000224 regulation of testosterone biosynthetic process
• GO:2000353 positive regulation of endothelial cell apoptotic process
• GO:2000379 positive regulation of reactive oxygen species metabolic process

Cellular Component

• GO:0005634 nucleus
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0070062 extracellular exosome

External links

• PDB: RCSB:4h7c, PDBe:4h7c, PDBj:4h7c
• PDBsum: 4h7c
• PubMed: 23454516
• UniProt: P42330|AK1C3_HUMAN Aldo-keto reductase family 1 member C3 (Gene Name=AKR1C3)