Structure of rabbit-muscle glyceraldehyde-3-phosphate dehydrogenase.
The crystal structure of the tetrameric form of D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) isolated from rabbit muscle was solved at 2.4 A resolution after careful dynamic light-scattering experiments to find a suitable buffer for crystallization trials. The refined model has a crystallographic R factor of 20.3%. Here, the first detailed model of a mammalian GAPDH is presented. The cofactor NAD(+) (nicotinamide adenine dinucleotide) is bound to two subunits of the tetrameric enzyme, which is consistent with the negative cooperativity of NAD(+) binding to this enzyme. The structure of rabbit-muscle GAPDH is of interest because it shares 91% sequence identity with the human enzyme; human GAPDH is a potential target for the development of anti-apoptotic drugs. In addition, differences in the cofactor-binding pocket compared with the homology-model structure of GAPDH from the malaria parasite Plasmodium falciparum could be exploited in order to develop novel selective and potential antimalaria drugs.
Cowan-Jacob
Sandra W
SW
Novartis Pharma AG, Core Technology Area, Analytics and Biomolecular Structure, CH-4002 Basel, Switzerland.
Kaufmann
Markus
M
Anselmo
Anthony N
AN
Stark
Wilhelm
W
Grütter
Markus G
MG
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011817:Rabbits; D016415:Sequence Alignment; D055672:Static Electricity
D009124:Muscle Proteins; D021122:Protein Subunits; D009243:NAD; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases