Comparison of 17β‐estradiol structures from x‐ray diffraction and solution NMR

The NMR‐derived structure of estrogen (17β‐estradiol, E2 ), the drug of choice for postmenopausal women, was compared with a recent literature crystal x‐ray structure of Fab‐bound E2 . 1 H and 13 C NMR spectra of E2 were acquired in DMSO‐ d 6 . Assignments were obtained from an analysis of DQF‐COSY, TOCSY, HETCOR, HMQC and HMBC 2D NMR spectra. The 1 H and 13 C NMR assignments are the first reported for E2 in DMSO‐ d 6 . Two solution structures, S1 and S2 , were obtained with molecular modeling using NOE constraints. S1 overlaps with the crystal structure for all rings. S2 shows prominent differences in the C‐ring (C9C11C12C13) segment, which deviates from a chair conformation, and excellent overlap in the A‐, B‐ and D‐rings of E2 . The C‐ring in S2 adopts a boat conformation as opposed to a chair conformation in the x‐ray and S1 structures. The S2 structure is about 6° more twisted than the bound x‐ray and S1 models. The S1, S2 and x‐ray structures had ring bowing values of 10.1 ± 0.3, 11 ± 1 and 10.37°, respectively. Of the 100 solution conformers generated, 83 had S1 conformation and 17 had S2 conformation, with average internal energies of 112 ± 2 and 141 ± 2 kcal mol −1 , respectively. The 100 S1 ‐ and S2 ‐ derived conformers showed a r.m.s.d. of 0.72 Å for all atoms. The x‐ray, S1 and S2 C18O17 distances were 2.93, 2.92 ± 0.01 and 2.93 ± 0.01 Å, respectively, and the O3O17 distances were 11.06, 11.18 ± 0.12, and 10.89 ± 0.05 Å, respectively. Copyright © 2005 John Wiley & Sons, Ltd.