HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Structure of Nm23-H1 under oxidative conditions.

Abstract
Nm23-H1/NDPK-A, a tumour metastasis suppressor, is a multifunctional housekeeping enzyme with nucleoside diphosphate kinase activity. Hexameric Nm23-H1 is required for suppression of tumour metastasis and it is dissociated into dimers under oxidative conditions. Here, the crystal structure of oxidized Nm23-H1 is presented. It reveals the formation of an intramolecular disulfide bond between Cys4 and Cys145 that triggers a large conformational change that destabilizes the hexameric state. The dependence of the dissociation dynamics on the H2O2 concentration was determined using hydrogen/deuterium-exchange experiments. The quaternary conformational change provides a suitable environment for the oxidation of Cys109 to sulfonic acid, as demonstrated by peptide sequencing using nanoUPLC-ESI-q-TOF tandem MS. From these and other data, it is proposed that the molecular and cellular functions of Nm23-H1 are regulated by a series of oxidative modifications coupled to its oligomeric states and that the modified cysteines are resolvable by NADPH-dependent reduction systems. These findings broaden the understanding of the complicated enzyme-regulatory mechanisms that operate under oxidative conditions.
AuthorsMi-Sun Kim, Jaeho Jeong, Jihye Jeong, Dong-Hae Shin, Kong-Joo Lee
JournalActa crystallographica. Section D, Biological crystallography (Acta Crystallogr D Biol Crystallogr) Vol. 69 Issue Pt 4 Pg. 669-80 (Apr 2013) ISSN: 1399-0047 [Electronic] United States
PMID23519676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cross-Linking Reagents
  • Disulfides
  • NM23 Nucleoside Diphosphate Kinases
  • NME1 protein, human
  • Cysteine
Topics
  • Amino Acid Sequence
  • Cross-Linking Reagents (chemistry)
  • Crystallography, X-Ray
  • Cysteine (chemistry, genetics)
  • Disulfides (chemistry)
  • Humans
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutation
  • NM23 Nucleoside Diphosphate Kinases (chemistry, genetics)
  • Oxidative Stress (genetics)
  • Protein Conformation
  • Protein Stability

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: