2V0A

Atomic resolution crystal structure of Human Superoxide Dismutase

Summary for 2V0A

• Entry DOI: 10.2210/pdb2v0a/pdb
• Related: 1AZV 1BA9 1DSW 1FUN 1HL4 1HL5 1KMG 1L3N 1MFM 1N18 1N19 1OEZ 1OZT 1OZU 1P1V 1PTZ 1PU0 1RK7 1SOS 1SPD 1UXL 1UXM 2AF2 2C9S 2C9U 2C9V 4SOD
• Descriptor: SUPEROXIDE DISMUTASE, COPPER (II) ION, ZINC ION, ... (6 entities in total)
• Functional Keywords: disease mutation, molecular dinamics, amyotrophic lateral sclerosis, zn superoxide dismutase, metal-binding, oxioreductase, oxidoreductase, zinc, copper, human cu, acetylation, antioxidant
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P00441
• Total number of polymer chains: 2
• Total formula weight: 32260.26

Authors

Strange, R.W.,Antonyuk, S.,Yong, C.W.,Smith, W.,Hasnain, S.S. (deposition date: 2007-05-11, release date: 2007-06-19, Last modification date: 2024-11-13)

Primary citation

Strange, R.W.,Yong, C.W.,Smith, W.,Hasnain, S.S.
Molecular Dynamics Using Atomic-Resolution Structure Reveal Structural Fluctuations that May Lead to Polymerization of Human Cu-Zn Superoxide Dismutase.
Proc.Natl.Acad.Sci.USA, 104:10040-, 2007

PubMed Abstract: Mutations of the gene encoding Cu-Zn superoxide dismutase (SOD1) cause 20% of the familial cases of the progressive neurodegenerative disease ALS. A growing body of evidence suggests that in familial ALS (FALS) it is the molecular behavior of the metal-depleted SOD1 dimer that leads to a gain of toxic properties by misfolding, unfolding, and aggregation. Structural studies have so far provided static snapshots on the behavior of the wild-type enzyme and some of the FALS mutants. New approaches are required to map out the structural trajectories of the molecule. Here, using our 1.15-A resolution structure of fully metallated human SOD1 and highly parallelized molecular dynamics code on a high-performance capability computer, we have undertaken molecular dynamics calculations to 4,000 ps to reveal the first stages of misfolding caused by metal deletion. Large spatial and temporal fluctuations of the "electrostatic" and "Zn-binding" loops adjacent to the metal-binding sites are observed in the apo-enzyme relative to the fully metallated dimer. These early misfolding events expose the beta-barrels of the dimer to the external environment, allowing close interactions with adjacent molecules. Protection of the beta-edge of the protein can be partially restored by incorporating a single Zn molecule per dimer. These calculations reveal an essential step in the formation of the experimentally observed self-aggregations of metal-depleted FALS mutant SOD1. This result also has implications for the role of demetallated wild-type SOD1 in sporadic cases of ALS, for which the molecular cause still remains undiscovered.

PubMed: 17548825
DOI: 10.1073/PNAS.0703857104

Experimental method

X-RAY DIFFRACTION (1.15 Å)