Structure of deoxyhemoglobin a crystals grown from polyethylene glycol solutions

Ward, Keith B.; Wishner, B.C.; Lattman, Eaton E.; Love, Warner E.

doi:10.1016/s0022-2836(75)80107-0

Cited by 96 publications

(41 citation statements)

References 35 publications

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“…Previously it had mainly been used for fractional precipitation (Ward et al, 1975). The steric exclusion mechanism of this precipitant was correctly identified as being similar to that of dextran reported by Torvard Laurent (Laurent, 1963).…”

Section: Introductionsupporting

confidence: 67%

Protein crystallization for drug design in the last 50 years

Stura¹

2015

Arbor

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ABSTRACT:We live in an era where we expect to be able to visit our doctor and obtain a pill to cure any ailment from which we suffer. Yet, this is still not the case. Many of the current cures are still derived from natural sources although new drugs are increasingly the result of intelligent design. In this process, X-ray protein crystallography now plays a major and effective role in the discovery of new treatments. The developments that have made this possible have evolved during the past fifty years. The methods for crystallizing macromolecules and determining their structures by X-ray crystallography have been automated and the speed for Xray data acquisition is several orders of magnitude faster. Fifty years ago it took several years to solve a single structure. Now, several protein-ligand complexes can be determined in single day. High-throughput crystallography is considered to be a great asset to the drug discovery process, providing a fast way to tailor drug candidates to their targets by analysing their binding mode in detail. Crystallization remains the main challenge.KEYWORDS: Drug design, crystallization. RESUMEN:Vivimos en una época en la que esperamos ir al médico y obtener una pastilla para curar cualquier dolencia que padezcamos; por desgracia, esta expectativa no es real. Aunque muchos de los remedios en uso provienen de fuentes naturales, la mayoría de los nuevos medicamentos son el resultado de la investigación científica. En el proceso de diseño y descubrimiento de fármacos, la cristalografía de proteínas juega un papel central. Los conocimientos que han hecho esto posible han venido evolucionando desde hace cincuenta años aproximadamente. Los métodos de cristalización de macromoléculas y la determinación de sus estructuras a través de la cristalografía de rayos X han sido automatizados y miniaturizados y la velocidad de la adquisición de datos de difracción ha aumentado en varios órdenes de magnitud. Si hace cincuenta años la resolución de una sola estructura podría llevar varios años, actualmente se pueden determinar las estructuras de varios complejos proteína-ligando en un solo día. La cristalografía de alto rendimiento hoy día es un gran recurso en el proceso del descubrimiento de fármacos pues proporciona una manera rápida y precisa de adaptar los fármacos candidatos a las dianas mediante el análisis de su modo de unión. La cristalización sigue siendo el principal desafío.PALABRAS CLAVE: diseño de fármacos, cristalización.

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Section: Introductionsupporting

confidence: 67%

Protein crystallization for drug design in the last 50 years

Stura¹

2015

Arbor

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“…The rotation search was limited to an Euler space of a , 0-180"; @, O-90"; y, 0-180". The translation search was performed using both a Patterson search in the Harker sections of space group P21212 (Crowther & Blow, 1967) and an independent R-factor search (Ward et al, 1975) with data between 10 and 5.3 A. The rotation and translation parameters were jointly refined using the R-factor minimization procedure RMINIM (Ward et al, 1975).…”

Section: Data Collectionmentioning

confidence: 99%

Comparison of the crystal structures of genetically engineered human manganese superoxide dismutase and manganese superoxide dismutase from thermus thermophilus: Differences in dimer–dimer interaction

et al. 1993

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The three‐dimensional X‐ray structure of a recombinant human mitochondrial manganese superoxide dismutase (MnSOD) (chain length 198 residues) was determined by the method of molecular replacement using the related structure of MnSOD from Thermus thermophilus as a search model. This tetrameric human MnSOD crystallizes in space group P21212 with a dimer in the asymmetric unit (Wagner, U.G., Werber, M.M., Beck, Y., Hartman, J.R., Frolow, F., & Sussman, J.L., 1989, J. Mol. Biol. 206, 787–788). Refinement of the protein structure (3, 148 atoms with Mn and no solvents), with restraints maintaining noncrystallographic symmetry, converged at an R‐factor of 0.207 using all data from 8.0 to 3.2 Å resolution and group thermal parameters. The monomer–monomer interactions typical of bacterial Fe‐ and Mn‐containing SODs are retained in the human enzyme, but the dimer–dimer interactions that form the tetramer are very different from those found in the structure of MnSOD from T. thermophilus. In human MnSOD one of the dimers is rotated by 84° relative to its equivalent in the thermophile enzyme. As a result the monomers are arranged in an approximately tetrahedral array, the dimer–dimer packing is more intimate than observed in the bacterial MnSOD from T. thermophilus, and the dimers interdigitate. The metal—ligand interactions, determined by refinement and verified by computation of omit maps, are identical to those observed in T. thermophilus MnSOD.

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“…Table 3 summarizes the results of the final stage of the translation searches. Interestingly, the results of the --114,122.5,-18 --112.5,122.5,--17.5 --112,125,--15 --113.5,122.5,-- 62.5,57.5,197 65,55,195 65,57,195 66,57.5,196 -18 --112,125,-17 --112,124,--16 --114,124,--19 height 54 63 69 44 Peak 2 : a,p, y (o) 65,55,196 65,55,200 67.5,55,195 68,56,196 tetramer, constructed by rotation of the aft dimer about the y axis the dimers have a common origin and the coordinates of the R factor minima should be identical (Ward et al, 1975). The agreement between this structure and deoxyhaemoglobin data fully confirmed these expectations.…”

Section: Resultsmentioning

confidence: 99%

“…The structure of deoxyhaemoglobin from polyethylene glycol has been solved by Ward, Wishner, Lattman & Love (1975) using the molecular replacement method. However, these authors encountered some difficulties, pointing out that the rotation function maps (Lattman & Love, 1970) gave convincing answers only when the whole haemoglobin tetramer was used as the search unit.…”

Section: Introduction'mentioning

confidence: 99%

“…There was some possibility that the quaternary structure of haemoglobin in these crystals was not the J~ conformation owing to the presence of oxygen. We therefore decided to find out whether methods other than those used by Ward et aL (1975), i.e. the fast rotation function (Crowther, 1972) and residual-type translation function (Nixon & North, 1976), would allow for the independent positioning of the aft dimers, and hence for the direct study of the quaternary structure of haemoglobin.…”

Section: Introduction'mentioning

confidence: 99%

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