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Milestones in Crystallography and Drug Design
Jenny P. GluskerFox Chase Cancer CenterPhiladelphia, PA 19111 USA
1. Determination of molecular structures by X-ray diffraction of crystals
2. Development of user-friendly computers
3. Their convergence to DRUG DESIGN
Seeing moleculesElectron microscopy X-ray diffraction of crystals
Early milestones in structure analysis
1. Discovery of X rays1895 Wilhelm Conrad RöntgenNobel Prize (physics) 1901Nature 53, 274 (1896)
2. Diffraction of X rays1912 Max Theodor Felix von LaueNobel Prize (physics) 1914Sitzungsber. Bayer. Akad. Wiss. Munchen p. 303 (1912)
3. Structure determination1913 William Henry Bragg & William Lawrence BraggNobel Prize (physics) 1915Proc. Roy. Soc. A89, 248 (1913)
Early X-ray photograph(Röntgen, 1895)
1895
Diffraction by a sieve anda crystalline virus
tobacco necrosis virus crystalcourtesy R.W.G. Wyckoff
photograph of a point sourceof light taken through a sieve
1958
The first X-ray diffraction photographs of crystals
(Friedrich and Knipping, 1912)
1912
Apparatus for X-ray diffraction
detectionsystem
crystal
source ofX rays
Sodium chloride structure
W. L. Bragg. Proc. Roy. Soc. A89, 248 (1913)
1913
Sodium and potassium chlorides
KCl
NaCl
KCl has larger unit cell than NaCl, therefore diffraction lines are closer for KCl
1913
Electron-density maps and phases
Information from X-ray diffraction
1. Angles of diffracted beams give the unit-cell dimensions
2. Orders of diffraction (h,k,l) give the periodicities of the electron-density waves
3. Intensities of diffracted beams give amplitudesof electron-density waves and can lead toatomic positions if the PHASE PROBLEMcan be solved
1930
Patterson functionpotassium dihydrogen phosphate
1930
19311931
1931
1934
1936
1930
Steroid structure (Bernal)
Wieland and Windaus formulae
Bernal, RosenheimKing formula
Wieland, Daneformula(also crystal structure)
HO
1932
Absolute configuration J.M. Bijvoet Nature 168, 271 (1951)
1951
Absolute configurationJ. M. Bijvoet
1951
Penicillin chemical formula
S
N
HOOCCH3
CH3
O
NH
CH2Ph
O
H
H
S
HN
HOOC
CH3
CH3
N
O
O
CH2Ph
H
H
1949
-lactam oxazolone
Penicillin
Penicillin G in penicillin acylase 1FXV Protein Eng. 13, 857 (2000) and1GM7 J. Mol. Biol. 313, 139 (2001)
Morphine
HO
O
HO
H
N
CH3
morphine
MORPHI Mackay & Hodgkin J.Chem. Soc. 3261 (1955)MORPHM Bye Acta Chem. Scand. B30, 549 (1976)
1955
Computing of the time
Cambridge EDSAC 2Computer 1960
1960
Cosine function,Beevers-Lipson strip and IBMpunched card
Patterson projection of whalemyoglobin
Direct methods
Electron-density maps and phases
Hexamethylbenzene
K. Lonsdale. Nature 122, 810 (1928)
h k l7 -3 0 3 4 04 -7 0 intense(triplet)
1928
Vitamin B12 coenzyme structure
Hodgkin. Nature 176, 325 (1955),
Vitamin B12 coenzyme
1955
Hodgkin. Nature 176, 325 (1955), Proc. Roy. Soc. A303, 45 (1968)
B DNA fibers
1953
Myoglobin
Kendrew and co-workers Nature 185, 422 (1960)
1960
Cytochrome P450
1985
Biochem. 26,8165 (1987)
Lysozyme with polysaccharide
1966
Sci. Amer. 215, 75 (1966)
Dihydrofolate reductase
A substrate analoguedoes not always bindin the same way as the substrate
1977
Science 197, 452 (1977)
Transition states
Linus Pauling, C&E News 24, 1375 (1946)
A enzyme lowers the energy barriers of a reaction by preferentially stabilizing the transition state of the substrate during the reaction rather than the ground state of that substrate
1946
Intermolecular interactions
Rosenfield JACS 99 4860 (1977)
1977
Intermolecular interactions
Murray-RustJACS 106, 1018 (1984)
1984
DNA interactions
SeemanPNAS 73, 804 (1976)
1976
Following reactionsBurgi, Dunitz, Shefter
Burgi, DunitzShefter JACS 95, 5065 (1973)
1973
Following reactionsLaue method
(Nature 329, 178 (1987)
1
3 4
2
1987
Homology modeling -secretaseWild-type beta secretase Swedish mutant
(better substrate)
Dunbrack, J. Mol. Biol. 300, 241 (2000)
2000