2f3r

Crystal Structure Of E.coli Guanylate Kinase In Complex With Ap5GCrystal Structure Of E.coli Guanylate Kinase In Complex With Ap5G

Structural highlights 2f3r is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KGUA_ECOLI Essential for recycling GMP and indirectly, cGMP. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Guanosine monophosphate kinases (GMPK), by catalyzing the phosphorylation of GMP or dGMP, are of dual potential in assisting the activation of anti-viral prodrugs or as candidates for antibiotic strategies. Human GMPK is an obligate step for the activation of acyclic guanosine analogs, such as ganciclovir, which necessitate efficient phosphorylation, while GMPK from bacterial pathogens, in which this enzyme is essential, are potential targets for therapeutic inhibition. Here we analyze these two aspects of GMPK activity with the crystal structures of Escherichia coli GMPK in complex with ganciclovir-monophosphate (GCV-MP) and with a bi-substrate inhibitor, Ap5G. GCV-MP binds as GMP to the GMP-binding domain, which is identical in E. coli and human GMPKs, but unlike the natural substrate fails to stabilize the closed, catalytically-competent conformation of this domain. Comparison with GMP- and GDP-bound GMPK structures identifies the 2'hydroxyl of the ribose moiety as responsible for hooking the GMP-binding domain onto the CORE domain. Absence of this hydroxyl in GCV-MP impairs the stabilization of the active conformation, and explains why GCV-MP is phosphorylated less efficiently than GMP, but as efficiently as dGMP. In contrast, Ap5G is an efficient inhibitor of GMPK. The crystal structure shows that Ap5G locks an incompletely closed conformation of the enzyme, in which the adenine moiety is located outside its expected binding site. Instead, it binds at a subunit interface that is unique to the bacterial enzyme, which is in equilibrium between a dimeric and an hexameric form in solution. This suggests that inhibitors could be designed to bind at this interface such as to prevent nucleotide-induced domain closure. Altogether, these complexes point to domain motions as critical components to be evaluated in therapeutic strategies targeting NMP kinases, with opposite effects depending on whether efficient phosphorylation or inhibition is being sought after. Crystal structures of GMP kinase in complex with ganciclovir monophosphate and Ap5G.,Hible G, Daalova P, Gilles AM, Cherfils J Biochimie. 2006 Sep;88(9):1157-64. Epub 2006 Apr 27. PMID:16690197 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Guanylate kinase 3D structures

spinqualitylabelsall models 2f3r, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image