2DGN

Mouse Muscle Adenylosuccinate Synthetase partially ligated complex with GTP, 2'-deoxy-IMP

Summary for 2DGN

• Entry DOI: 10.2210/pdb2dgn/pdb
• Related: 1LNY
• Descriptor: Adenylosuccinate synthetase isozyme 1, MAGNESIUM ION, 9-(2-DEOXY-5-O-PHOSPHONO-BETA-D-ERYTHRO-PENTOFURANOSYL)-6-(PHOSPHONOOXY)-9H-PURINE, ... (5 entities in total)
• Functional Keywords: adenylosuccinate synthetase, gtp, adss1, 2'-deoxy-imp, ligase
• Biological source: Mus musculus (house mouse)
• Cellular location: Cytoplasm: P28650
• Total number of polymer chains: 1
• Total formula weight: 51200.99

Authors

Iancu, C.V.,Zhou, Y.,Borza, T.,Fromm, H.J.,Honzatko, R.B. (deposition date: 2006-03-15, release date: 2006-09-15, Last modification date: 2024-03-13)

Primary citation

Iancu, C.V.,Zhou, Y.,Borza, T.,Fromm, H.J.,Honzatko, R.B.
Cavitation as a mechanism of substrate discrimination by adenylosuccinate synthetases.
Biochemistry, 45:11703-11711, 2006

PubMed Abstract: Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, coupling L-aspartate and IMP to form adenylosuccinate. Km values of IMP and 2'-deoxy-IMP are nearly identical with each substrate supporting comparable maximal velocities. Nonetheless, the Km value for L-aspartate and the Ki value for hadacidin (a competitive inhibitor with respect to L-aspartate) are 29-57-fold lower in the presence of IMP than in the presence of 2'-deoxy-IMP. Crystal structures of the synthetase ligated with hadacidin, GDP, and either 6-phosphoryl-IMP or 2'-deoxy-6-phosphoryl-IMP are identical except for the presence of a cavity normally occupied by the 2'-hydroxyl group of IMP. In the presence of 6-phosphoryl-IMP and GDP (hadacidin absent), the L-aspartate pocket can retain its fully ligated conformation, forming hydrogen bonds between the 2'-hydroxyl group of IMP and sequence-invariant residues. In the presence of 2'-deoxy-6-phosphoryl-IMP and GDP, however, the L-aspartate pocket is poorly ordered. The absence of the 2'-hydroxyl group of the deoxyribonucleotide may destabilize binding of the ligand to the L-aspartate pocket by disrupting hydrogen bonds that maintain a favorable protein conformation and by the introduction of a cavity into the fully ligated active site. At an approximate energy cost of 2.2 kcal/mol, the unfavorable thermodynamics of cavity formation may be the major factor in destabilizing ligands at the L-aspartate pocket.

PubMed: 16981730
DOI: 10.1021/bi0607498

Experimental method

X-RAY DIFFRACTION (2.4 Å)