Crystal structure of human guanosine monophosphate reductase 2 (GMPR2) in complex with GMP.
Guanosine monophosphate reductase (GMPR) catalyzes the irreversible and NADPH-dependent reductive deamination of GMP to IMP, and plays a critical role in re-utilization of free intracellular bases and purine nucleosides. Here, we report the first crystal structure of human GMP reductase 2 (hGMPR2) in complex with GMP at 3.0 A resolution. The protein forms a tetramer composed of subunits adopting the ubiquitous (alpha/beta)8 barrel fold. Interestingly, the substrate GMP is bound to hGMPR2 through interactions with Met269, Ser270, Arg286, Ser288, and Gly290; this makes the conformation of the adjacent flexible binding region (residues 268-289) fixed, much like a door on a hinge. Structure comparison and sequence alignment analyses show that the conformation of the active site loop (residues 179-187) is similar to those of hGMPR1 and inosine monophosphate dehydrogenases (IMPDHs). We propose that Cys186 is the potential active site, and that the conformation of the loop (residues 129-133) suggests a preference for the coenzyme NADPH over NADH. This structure provides important information towards understanding the functions of members of the GMPR family.
Li
Jixi
J
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
Wei
Zhiyi
Z
Zheng
Mei
M
Gu
Xing
X
Deng
Yingfeng
Y
Qiu
Rui
R
Chen
Fei
F
Ji
Chaoneng
C
Gong
Weimin
W
Xie
Yi
Y
Mao
Yumin
Y
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D050899:GMP Reductase; D006157:Guanosine Monophosphate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D021122:Protein Subunits; D006157:Guanosine Monophosphate; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D009247:NADH, NADPH Oxidoreductases; D050899:GMP Reductase; C469406:GMPR2 protein, human