Structure of Human Adenosine Kinase at 1.5 Å Resolution
详细信息 查看全文
- 作者：Irimpan I. Mathews ; Mark D. Erion ; and Steven E. Ealick
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：November 10, 1998
- 年：1998
- 卷：37
- 期：45
- 页码：15607 - 15620
- 全文大小：364K
- 年卷期：v.37,no.45(November 10, 1998)
- ISSN：1520-4995
文摘
Adenosine kinase (AK) is a key enzyme in the regulation of extracellular adenosine andintracellular adenylate levels. Inhibitors of adenosine kinase elevate adenosine to levels that activatenearby adenosine receptors and produce a wide variety of therapeutically beneficial activities. Accordingly,AK is a promising target for new analgesic, neuroprotective, and cardioprotective agents. We determinedthe structure of human adenosine kinase by X-ray crystallography using MAD phasing techniques andrefined the structure to 1.5 Å resolution. The enzyme structure consisted of one large 
/
domain withnine -strands, eight -helices, and one small /-domain with five -strands and two -helices. Theactive site is formed along the edge of the -sheet in the large domain while the small domain acts as alid to cover the upper face of the active site. The overall structure is similar to the recently reportedstructure of ribokinase from Escherichia coli [Sigrell et al. (1998) Structure 6, 183-193]. The structureof ribokinase was determined at 1.8 Å resolution and represents the first structure of a new family ofcarbohydrate kinases. Two molecules of adenosine were present in the AK crystal structure with oneadenosine molecule located in a site that matches the ribose site in ribokinase and probably represents thesubstrate-binding site. The second adenosine site overlaps the ADP site in ribokinase and probablyrepresents the ATP site. A Mg2+ ion binding site is observed in a trough between the two adenosinesites. The structure of the active site is consistent with the observed substrate specificity. The active-sitemodel suggests that Asp300 is an important catalytic residue involved in the deprotonation of the 5'-hydroxyl during the phosphate transfer.
/ domain withnine -strands, eight -helices, and one small /-domain with five -strands and two -helices. Theactive site is formed along the edge of the -sheet in the large domain while the small domain acts as alid to cover the upper face of the active site. The overall structure is similar to the recently reportedstructure of ribokinase from Escherichia coli [Sigrell et al. (1998) Structure 6, 183-193]. The structureof ribokinase was determined at 1.8 Å resolution and represents the first structure of a new family ofcarbohydrate kinases. Two molecules of adenosine were present in the AK crystal structure with oneadenosine molecule located in a site that matches the ribose site in ribokinase and probably represents thesubstrate-binding site. The second adenosine site overlaps the ADP site in ribokinase and probablyrepresents the ATP site. A Mg2+ ion binding site is observed in a trough between the two adenosinesites. The structure of the active site is consistent with the observed substrate specificity. The active-sitemodel suggests that Asp300 is an important catalytic residue involved in the deprotonation of the 5'-hydroxyl during the phosphate transfer.