Structure of PDB 1hvy Chain A Binding Site BS01

Receptor Information

>1hvy Chain A (length=288) Species: 9606 (Homo sapiens)

PPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFGMQARYSLRDEFPLLT
TKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDSLGFST
REEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDR
RIIMCAWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPF
NIASYALLTYMIAHITGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRP
FPKLRILRKVEKIDDFKAEDFQIEGYNPHPTIKMEMAV

Ligand information

• Ligand ID: D16
• InChI: InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1
• InChIKey: IVTVGDXNLFLDRM-HNNXBMFYSA-N
• SMILES:
  ACDLabs 12.01: O=C(c3sc(N(C)Cc2ccc1NC(=NC(=O)c1c2)C)cc3)NC(C(=O)O)CCC(=O)O
  CACTVS 3.370: CN(Cc1ccc2NC(=NC(=O)c2c1)C)c3sc(cc3)C(=O)N[CH](CCC(O)=O)C(O)=O
  OpenEye OEToolkits 1.7.6: CC1=NC(=O)c2cc(ccc2N1)CN(C)c3ccc(s3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
  CACTVS 3.370: CN(Cc1ccc2NC(=NC(=O)c2c1)C)c3sc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O
  OpenEye OEToolkits 1.7.6: CC1=NC(=O)c2cc(ccc2N1)CN(C)c3ccc(s3)C(=O)NC(CCC(=O)O)C(=O)O
• Formula: C21 H22 N4 O6 S
• Name: TOMUDEX;
  ZD1694;
  Raltitrexed
• ChEMBL: CHEMBL225071
• DrugBank: DB00293
• ZINC: ZINC000003832372
• PDB chain: 1hvy Chain A Residue 414

Receptor-Ligand Complex Structure

Structure summary

• PDB: 1hvy Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
• Resolution: 1.9 Å
• Binding residue (original residue number in PDB): F80 I108 W109 D218 L221 G222 F225 Y258 M311
• Binding residue (residue number reindexed from 1): F55 I83 W84 D193 L196 G197 F200 Y233 M286
• Annotation score: 1
• Binding affinity: PDBbind-CN: -logKd/Ki=6.54,IC50=0.29uM
  BindingDB: IC50=29000nM

Enzymatic activity

• Catalytic site (original residue number in PDB): E87 W109 Y135 C195 R215 D218
• Catalytic site (residue number reindexed from 1): E62 W84 Y110 C170 R190 D193
• Enzyme Commision number: 2.1.1.45: thymidylate synthase.

Gene Ontology

Molecular Function

• GO:0000900 mRNA regulatory element binding translation repressor activity
• GO:0003729 mRNA binding
• GO:0004799 thymidylate synthase activity
• GO:0005542 folic acid binding
• GO:0008168 methyltransferase activity
• GO:0016741 transferase activity, transferring one-carbon groups
• GO:0042803 protein homodimerization activity
• GO:1901363 heterocyclic compound binding
• GO:1990825 sequence-specific mRNA binding

Biological Process

• GO:0006206 pyrimidine nucleobase metabolic process
• GO:0006231 dTMP biosynthetic process
• GO:0006235 dTTP biosynthetic process
• GO:0006417 regulation of translation
• GO:0007623 circadian rhythm
• GO:0009165 nucleotide biosynthetic process
• GO:0009410 response to xenobiotic stimulus
• GO:0009636 response to toxic substance
• GO:0014070 response to organic cyclic compound
• GO:0017148 negative regulation of translation
• GO:0019860 uracil metabolic process
• GO:0032259 methylation
• GO:0032570 response to progesterone
• GO:0033189 response to vitamin A
• GO:0034097 response to cytokine
• GO:0035999 tetrahydrofolate interconversion
• GO:0045471 response to ethanol
• GO:0046653 tetrahydrofolate metabolic process
• GO:0046683 response to organophosphorus
• GO:0048589 developmental growth
• GO:0051216 cartilage development
• GO:0051384 response to glucocorticoid
• GO:0051593 response to folic acid
• GO:0060574 intestinal epithelial cell maturation
• GO:0071897 DNA biosynthetic process
• GO:0097421 liver regeneration

Cellular Component

• GO:0005634 nucleus
• GO:0005737 cytoplasm
• GO:0005739 mitochondrion
• GO:0005743 mitochondrial inner membrane
• GO:0005759 mitochondrial matrix
• GO:0005829 cytosol

External links

• PDB: RCSB:1hvy, PDBe:1hvy, PDBj:1hvy
• PDBsum: 1hvy
• PubMed: 11329255
• UniProt: P04818|TYSY_HUMAN Thymidylate synthase (Gene Name=TYMS)