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M H Levitt

Publications and source records attributed to M H Levitt.

31 records · Page 2Linked to original sources
PubMed1998

13C and 15N-chemical shift anisotropy of ampicillin and penicillin-V studied by 2D-PASS and CP/MAS NMR.

The principal values of the chemical shift tensors of all 13C and 15N sites in two antibiotics, ampicillin and penicillin-V, were determined by 2-dimensional phase adjusted spinning sideband (2D-PASS) and conventional CP/MAS experiments. The 13C and 15N chemical shift anisotropies (CSA), and their confidence limits, were evaluated using a Mathematica program. The CSA values suggest a revised assignment of the 2-methyl 13C sites in the case of ampicillin. We speculate on a relationship between the chemical shift principal values of many of the 13C and 15N sites and the beta-lactam ring conformation.

Ampicillin↗
PubMed1997

The conformation of an inhibitor bound to the gastric proton pump.

Substituted imidazo[1,2-a]pyridines are pharmaceutically important small molecule inhibitors of the gastric H+/K+-ATPase, the membrane-bound therapeutic target for peptic ulcer disease. A non-perturbing analytical technique, rotational resonance NMR spectroscopy, was used to measure a precise (to +/-0.2 A) distance between atomic sites in a substituted imidazo[1,2-a]pyridine, TMPIP, bound to H+/K+-ATPase at its high-affinity site in the intact, native membrane. The structural analysis of the enzyme-inhibitor complex revealed that the flexible moiety of TMPIP adopts a 'syn-type' conformation at its site of action. Hence, the conformation of an inhibitor has been resolved directly under near-physiological conditions, providing a sound experimental basis for rational design of many active compounds of pharmaceutical interest. Chemically restraining the flexible moiety of compounds like TMPIP in the syn-type binding conformation was found to increase activity by over 2 orders of magnitude. Such information is normally only available after extensive synthesis of related compounds and multiple screening approaches.

H(+)-K(+)-Exchanging ATPase↗
PubMed1997

Conformational transitions of the phosphodiester backbone in native DNA: two-dimensional magic-angle-spinning 31P-NMR of DNA fibers.

Solid-state 31P-NMR is used to investigate the orientation of the phosphodiester backbone in NaDNA-, LiDNA-, MgDNA-, and NaDNA-netropsin fibers. The results for A- and B-DNA agree with previous interpretations. We verify that the binding of netropsin to NaDNA stabilizes the B form, and find that in NaDNA, most of the phosphate groups adopt a conformation typical of the A form, although there are minor components with phosphate orientations close to the B form. For LiDNA and MgDNA samples, on the other hand, we find phosphate conformations that are in variance with previous models. These samples display x-ray diffraction patterns that correspond to C-DNA. However, we find two distinct phosphate orientations in these samples, one resembling that in B-DNA, and one displaying a twist of the PO4 groups about the O3-P-O4 bisectors. The latter conformation is not in accordance with previous models of C-DNA structure.

Crystallography, X-Ray↗
PubMed1994

Determination of internuclear distances and the orientation of functional groups by solid-state NMR: rotational resonance study of the conformation of retinal in bacteriorhodopsin.

We have used a new solid-state NMR technique--rotational resonance--to determine both internuclear distances and the relative orientations of chemical groups (dihedral angles) in retinal bound to bacteriorhodopsin (bR) and in retinoic acid model compounds. By matching the rotational resonance condition (delta = n omega r/2 pi, where delta is the difference in isotropic chemical shifts for two dipolar coupled spins, omega r/2 pi is the mechanical rotational frequency of the sample in the MAS experiment, and n is a small integer denoting the order of the resonance), we selectively reintroduce the dipolar coupling and enhance the rate of magnetization exchange. Spectroscopic data and theoretical simulations of the magnetization exchange trajectories for the 8,18-13C dipolar coupled pair in retinoic acid model compounds, crystallized in both the 6-s-cis and 6-s-trans forms, indicate that an accurate determination of the internuclear distance is possible. For the n = 1 resonance we find the distance determination to be reasonably independent of the relative orientation of the groups. In contrast, for the n = 2 resonance, there is a more pronounced dependence on the relative orientation of the groups which permits an estimate of the angle around the 6-s bond for the cis and trans forms to be 42 +/- 5 degrees and 90 +/- 10 degrees, respectively, in good agreement with crystallography. In bR we demonstrate that the 8-13C-18-13C distance is 4.1 A and the average 8-13C-16-13C/8-13C-17-13C distance is 3.3-3.5 A.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriorhodopsins↗
PubMed1993

High-resolution 1H NMR in solids with frequency-switched multiple-pulse sequences.

A new pulse sequence for abundant-spin NMR in solids, called FSLG240W, is demonstrated. The sequence employs phase-coherent frequency-switching of the rf irradiation to induce opposite rotations around the magic-angle axis in the rotating frame. Three 4 pi/3 rotations in one sense are followed by three 4 pi/3 rotations in the opposite sense. Observation windows separate each rotation. The pulse sequence cancels out the average dipolar Hamiltonian, the first-order correction terms, and the most deliterious second-order terms. The pulse sequence has a short cycle time and a high scaling factor kappa = 1/square root of 3, but is sensitive to rf inhomogeneity. We demonstrate slightly better resolution than either MREV8 or BR24 on a small spherical sample of L-alanine.

Alanine↗
PubMed1991

Determination of membrane protein structure by rotational resonance NMR: bacteriorhodopsin.

Rotationally resonant magnetization exchange, a new nuclear magnetic resonance (NMR) technique for measuring internuclear distances between like spins in solids, was used to determine the distance between the C-8 and C-18 carbons of retinal in two model compounds and in the membrane protein bacteriorhodopsin. Magnetization transfer between inequivalent spins with an isotropic shift separation, delta, is driven by magic angle spinning at a speed omega r that matches the rotational resonance condition delta = n omega r, where n is a small integer. The distances measured in this way for both the 6-s-cis- and 6-s-trans-retinoic acid model compounds agreed well with crystallographically known distances. In bacteriorhodopsin the exchange trajectory between C-8 and C-18 was in good agreement with the internuclear distance for a 6-s-trans configuration [4.2 angstroms (A)] and inconsistent with that for a 6-s-cis configuration (3.1 A). The results illustrate that rotational resonance can be used for structural studies in membrane proteins and in other situations where diffraction and solution NMR techniques yield limited information.

Bacteriorhodopsins↗
PubMed1977

Experimental pancreatic carcinogenesis. I. Morphogenesis of pancreatic adenocarcinoma in the Syrian golden hamster induced by N-nitroso-bis(2-hydroxypropyl)amine.

In serial sacrifice experiment, outbred male Syrian golden hamsters were treated once weekly for life with subcutaneous injections of N-nitroso-bis(2-hydroxypropyl) amine (DIPN). The pancreas was examined by high resolution light (1-micro sections) and transmission electron microscopy. Early nonspecific changes in all pancreatic epithelial cellular elements were followed by a progressive proliferation of intra- and interlobular duct cells, with the development of multicentric foci of cystic and papillary cystic adenomas, intraductal carcinomas, and invasive ductal neoplasms. These observations were consistent with multistage morphogenesis of pancreatic adenocarcinoma of ductal origin.

Adenocarcinoma↗