5070
Stereochemistry of Nucleic Acids and Their Constituents. XXVII.’ The Crystal Structure of 5’-Methyleneadenosine 3’,5’-Cyclic Monophosphonate Monohydrate, a Biologically Active Analog of the Secondary Hormonal Messenger Cyclic Adenosine 3’,5’-Monophosphate. Conformational “Rigidity” of the Furanose Ring in Cyclic Nucleotides M. Sundaralingam” and J. Abola Contribution f r o m the Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison, Wisconsin 53706. Received November I , 1971
Abstract: The crystal structure of the isosteric phosphonate analog of cyclic AMP has been determined using threemdimensional data measured on a diffractometer. The crystals belong to the orthorhoFbic system, space group P212121. The unit cell constants are: a = 10.755 (2), b = 8.869 (2), c = 15.198 (2) A, Z = 4, Dobsd= 1.578 g ~ m - Dcalod ~ , = 1.579 g ~ m - ~The . structure was solved by the use of the Patterson method and the application of the tangent formula. Refinement by the method of full-matrix least squares with anisotropic temperature factors for nonhydrogen atoms and isotropic temperature factors for the hydrogen atoms gave a final R of 0.04 for the 1199 observed reflections. The base displays the syn conformation with respect to rotation about the glycosyl bond, x being -125.8’. The constraints of the cyclization freeze the ribose into the conformation, T4(C(3’)endo-C(4’)-exo), which appears to be characteristic of the cyclic nucleotides. For a similar reason the bond distances and bond angles in the ribose ring show marked differences from those of the nucleotides themselves. The phosphonate ring is in the chair conformation and flattened at the phosphorus end. The molecule is a zwitterion with the base site N(l) protonated by a phosphonate hydrogen. The nucleotides are packed in a head-to-tail fashion and are involved in an intricate scheme of hydrogen bonding both to themselves and the water of crystallization. A comparison of the conformation of the analog is made with the available data on cyclic AMP and cyclic UMP.
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yclic adenosine 3 ’,5 ’-monophosphate (cyclic AMP) was discovered in 1960 by S ~ t h e r l a n d * who ,~ demonstrated that it acted as a link or “messenger” between a large number of different hormones and the control and regulatory mechanisms of the human body. Cyclic A M P dependent protein kinases occur in a wide variety of tissues throughout the animal kingdom. In recent years a number of structurally related analogs of cyclic A M P have been synthesized and tested for their biological activity. 4 , 5 Perhaps the most notable of these are the N(6)-substituted derivatives which have been found to be more specific in their action than the natural metabo1ite.j The 5 ’-methylene cyclic phosphonate analog of cyclic AMP, 1, is known to cause varying degrees of activation, with up t o 50% of the maximal velocity of the natural compound, of the different cyclic A M P dependent protein kinases.6-8 The present crystal-structure analysis of the 5 ’-methylene analog was undertaken to compare its molecular conformation with that of the natural metabolite, a pre( I ) For part XXVI of this series, see s. M. Hecht and M. Sundaralingam,J. Amer. Chem. Soc., 94,4314 (1972). (2) E. W. Sutherland and T. W. Rall, Pharmacol. Rec., 12,265 (1960). (3) G. A. Robinson, R . W. Butcher, and E. W. Sutherland, “Advances in Biochemical Psychopharmacology,” Academic Press, New York, N. Y., 1971. (4) K . Muneyama, R. J. Bauer, D. A. Shuman, R. I
