2i6a
Human Adenosine Kinase in Complex With 5'-Deoxy-5-Iodotubercidin
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OverviewOverview
Adenosine kinase (AK) is an enzyme responsible for converting endogenous, adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine, triphosphate- (ATP-) dependent manner. The structure of AK consists of two, domains, the first a large alpha/beta Rossmann-like nucleotide binding, domain that forms the ATP binding site, and a smaller mixed alpha/beta, domain, which, in combination with the larger domain, forms the ADO, binding site and the site of phosphoryl transfer. AK inhibitors have been, under investigation as antinociceptive, antiinflammatory, and, anticonvulsant as well as antiinfective agents. In this work, we report, the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two, classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the, inhibitor classes by a 30 degrees rotation of the small domain relative to, the large domain. This change in binding mode stabilizes an open and a, closed intermediate structural state and provide structural insight into, the transition required for catalysis. This results in a significant, rearrangement of both the protein active site and the orientation of the, alkynylpyrimidine ligand when compared to the observed orientation of, nucleosidic inhibitors or substrates.
About this StructureAbout this Structure
2I6A is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of human adenosine kinase inhibitor complexes reveal two distinct binding modes., Muchmore SW, Smith RA, Stewart AO, Cowart MD, Gomtsyan A, Matulenko MA, Yu H, Severin JM, Bhagwat SS, Lee CH, Kowaluk EA, Jarvis MF, Jakob CL, J Med Chem. 2006 Nov 16;49(23):6726-31. PMID:17154503
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