2C6Q

Crystal structure of human guanosine monophosphate reductase 2 GMPR2 in complex with IMP and NADPH

Summary for 2C6Q

• Entry DOI: 10.2210/pdb2c6q/pdb
• Related: 2BZN
• Descriptor: GMP REDUCTASE 2, INOSINIC ACID, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: tim barrel, metal-binding, nadp, oxidoreductase, potassium
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 8
• Total formula weight: 313263.94

Authors

Kursula, P.,Stenmark, P.,Arrowsmith, C.,Berglund, H.,Edwards, A.,Ehn, M.,Graslund, S.,Hammarstrom, M.,Hallberg, B.M.,Kotenyova, T.,Nilsson-Ehle, P.,Ogg, D.,Persson, C.,Sagemark, J.,Schuler, H.,Sundstrom, M.,Thorsell, A.,Weigelt, J.,Nordlund, P. (deposition date: 2005-11-11, release date: 2005-11-30, Last modification date: 2024-10-23)

Primary citation

Patton, G.C.,Stenmark, P.,Gollapalli, D.R.,Sevastik, R.,Kursula, P.,Flodin, S.,Schuler, H.,Swales, C.T.,Eklund, H.,Himo, F.,Nordlund, P.,Hedstrom, L.
Cofactor Mobility Determines Reaction Outcome in the Impdh and Gmpr (Beta-Alpha)(8) Barrel Enzymes.
Nat.Chem.Biol., 7:950-, 2011

PubMed Abstract: Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP* as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 Å from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.

PubMed: 22037469
DOI: 10.1038/NCHEMBIO.693

Experimental method

X-RAY DIFFRACTION (1.7 Å)