Solution structure of the variable-type domain of the receptor for advanced glycation end products: new insight into AGE-RAGE interaction.
Diabetes is defined by chronic hyperglycemia due to deficiency in insulin action. It has been found that the amount of advanced glycation end products (AGE) from the Maillard reaction between proteins and sugar molecules increases in blood of diabetic patients and furthermore that AGE binding to their cell surface receptor (RAGE) triggers both macrovascular and microvascular impairments to cause diabetic complications. Due to the clinical significance of the vascular complications, RAGE is currently a focus as an attractive target for drug discovery of candidates which interfere with AGE-RAGE binding to prevent the subsequent intracellular signaling related to pathogenical effects. Here, we determined the three-dimensional structure of the recombinant AGE-binding domain by using multidimensional heteronuclear NMR spectroscopy and showed that the domain assumes a structure similar to those of other immunoglobulin V-type domains. The site-directed mutagenesis studies identified the basic amino acids which play a key role in the AGE binding activities. Our results obtained from this study provide new insight into AGE-RAGE interaction.
Matsumoto
Shigeyuki
S
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yoshida
Takuya
T
Murata
Hiroko
H
Harada
Shusaku
S
Fujita
Naoko
N
Nakamura
Shota
S
Yamamoto
Yasuhiko
Y
Watanabe
Takuo
T
Yonekura
Hideto
H
Yamamoto
Hiroshi
H
Ohkubo
Tadayasu
T
Kobayashi
Yuji
Y
D000818:Animals; D002417:Cattle; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D012996:Solutions
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012996:Solutions; D012710:Serum Albumin, Bovine