4A7G

Structure of human I113T SOD1 mutant complexed with 4-methylpiperazin- 1-yl)quinazoline in the p21 space group.

Summary for 4A7G

• Entry DOI: 10.2210/pdb4a7g/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 2V0A 2VR6 2VR7 2VR8 2WKO 2WYT 2WYZ 2WZ0 2WZ5 2WZ6 2XJK 2XJL 4SOD
• Descriptor: SUPEROXIDE DISMUTASE [CU-ZN], SULFATE ION, 4-(4-METHYLPIPERAZIN-1-YL)QUINAZOLINE, ... (8 entities in total)
• Functional Keywords: oxidoreductase, amyotrophic lateral sclerosis, antioxidant, disease mutation, metal-binding, zn superoxide dismutase
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 33101.11

Authors

Wright, G.S.A.,Kershaw, N.M.,Sharma, R.,Antonyuk, S.V.,Strange, R.W.,Berry, N.G.,O'Neil, P.M.,Hasnain, S.S. (deposition date: 2011-11-14, release date: 2012-10-24, Last modification date: 2024-10-16)

Primary citation

Kershaw, N.M.,Wright, G.S.,Sharma, R.,Antonyuk, S.V.,Strange, R.W.,Berry, N.G.,O'Neill, P.M.,Hasnain, S.S.
X-ray crystallography and computational docking for the detection and development of protein-ligand interactions.
Curr.Med.Chem., 20:569-575, 2013

PubMed Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design.

PubMed: 23278398
DOI: 10.2174/0929867311320040008

Experimental method

X-RAY DIFFRACTION (1.24 Å)