Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 29 July 1977:
Vol. 197. no. 4302, pp. 452 - 455
DOI: 10.1126/science.17920
Prev | Table of Contents | Next

Articles

Science, Vol 197, Issue 4302, 452-455
Copyright © 1977 by American Association for the Advancement of Science

articles

Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate

DA Matthews, RA Alden, JT Bolin, ST Freer, R Hamlin, N Xuong, J Kraut, M Poe, M Williams, and K Hoogsteen

A central eight-stranded beta-pleated sheet is the main feature of the polypeptide backbone folding in dihydrofolate reductase. The innermost four strands and two bridging helices are geometrically similar to but are connected in a different way from those in the dinucleotide binding domains found in nicotinamide-adenine dinucleotide-linked dehydrogenases. Methotrexate is bound in a 15-angstrom-deep cavity with the pteridine ring buried in a primarily hydrophobic pocket, although a strong interaction occurs between the side chain of aspartic acid 27 and N(1), N(8), and the 2-amino group of methotrexate.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Elucidating the Germination Transcriptional Program Using Small Molecules.
G. W. Bassel, P. Fung, T.-f. F. Chow, J. A. Foong, N. J. Provart, and S. R. Cutler (2008)
Plant Physiology 147, 143-155
   Abstract »    Full Text »    PDF »
5-Methyltetrahydrofolate Is Bound in Intersubunit Areas of Rat Liver Folate-binding Protein Glycine N-Methyltransferase.
Z. Luka, S. Pakhomova, L. V. Loukachevitch, M. Egli, M. E. Newcomer, and C. Wagner (2007)
J. Biol. Chem. 282, 4069-4075
   Abstract »    Full Text »    PDF »
Limited Polymorphism in the Dihydropteroate Synthetase Gene (dhps) of Plasmodium vivax Isolates from Thailand.
M. Imwong, S. Pukrittayakamee, Q. Cheng, C. Moore, S. Looareesuwan, G. Snounou, N. J. White, and N. P. J. Day (2005)
Antimicrob. Agents Chemother. 49, 4393-4395
   Abstract »    Full Text »    PDF »
Here Be Dragons: Docking and Screening in an Uncharted Region of Chemical Space.
R. Brenk, J. J. Irwin, and B. K. Shoichet (2005)
J Biomol Screen 10, 667-674
   Abstract »    PDF »
Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance.
P. Kongsaeree, P. Khongsuk, U. Leartsakulpanich, P. Chitnumsub, B. Tarnchompoo, M. D. Walkinshaw, and Y. Yuthavong (2005)
PNAS 102, 13046-13051
   Abstract »    Full Text »    PDF »
Novel Point Mutations in the Dihydrofolate Reductase Gene of Plasmodium vivax: Evidence for Sequential Selection by Drug Pressure.
M. Imwong, S. Pukrittayakamee, L. Renia, F. Letourneur, J.-P. Charlieu, U. Leartsakulpanich, S. Looareesuwan, N. J. White, and G. Snounou (2003)
Antimicrob. Agents Chemother. 47, 1514-1521
   Abstract »    Full Text »    PDF »
Association of Genetic Mutations in Plasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates.
M. Imwong, S. Pukrittakayamee, S. Looareesuwan, G. Pasvol, J. Poirreiz, N. J. White, and G. Snounou (2001)
Antimicrob. Agents Chemother. 45, 3122-3127
   Abstract »    Full Text »    PDF »
Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil.
D. A. Fidock and T. E. Wellems (1997)
PNAS 94, 10931-10936
   Abstract »    Full Text »    PDF »
Structure-Based Strategies for Drug Design and Discovery.
I. D. Kuntz (1992)
Science 257, 1078-1082
   Abstract »    PDF »
Insights into enzyme function from studies on mutants of dihydrofolate reductase.
S. Benkovic, C. Fierke, and A. Naylor (1988)
Science 239, 1105-1110
   Abstract »    PDF »
Functional role of aspartic acid-27 in dihydrofolate reductase revealed by mutagenesis.
E. Howell, J. Villafranca, M. Warren, S. Oatley, and J Kraut (1986)
Science 231, 1123-1128
   Abstract »    PDF »
Directed mutagenesis of dihydrofolate reductase.
J. Villafranca, E. Howell, D. Voet, M. Strobel, R. Ogden, J. Abelson, and J Kraut (1983)
Science 222, 782-788
   Abstract »    PDF »
Folic acid: crystal structure and implications for enzyme binding.
D Mastropaolo, A Camerman, and N Camerman (1980)
Science 210, 334-336
   Abstract »    PDF »
Three-dimensional molecular modeling and drug design.
P Gund, J. Andose, J. Rhodes, and G. Smith (1980)
Science 208, 1425-1431
   Abstract »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)