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Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.

Publication ,  Journal Article
Strickland, CL; Windsor, WT; Syto, R; Wang, L; Bond, R; Wu, Z; Schwartz, J; Le, HV; Beese, LS; Weber, PC
Published in: Biochemistry
November 24, 1998

The crystallographic structure of acetyl-Cys-Val-Ile-selenoMet-COOH and alpha-hydroxyfarnesylphosphonic acid (alphaHFP) complexed with rat farnesyl protein transferase (FPT) (space group P61, a = b = 174. 13 A, c = 69.71 A, alpha = beta = 90 degrees, gamma = 120 degrees, Rfactor = 21.8%, Rfree = 29.2%, 2.5 A resolution) is reported. In the ternary complex, the bound substrates are within van der Waals contact of each other and the FPT enzyme. alphaHFP binds in an extended conformation in the active-site cavity where positively charged side chains and solvent molecules interact with the phosphate moiety and aromatic side chains pack adjacent to the isoprenoid chain. The backbone of the bound CaaX peptide adopts an extended conformation, and the side chains interact with both FPT and alphaHFP. The cysteine sulfur of the bound peptide coordinates the active-site zinc. Overall, peptide binding and recognition appear to be dominated by side-chain interactions. Comparison of the structures of the ternary complex and unliganded FPT [Park, H., Boduluri, S., Moomaw, J., Casey, P., and Beese, L. (1997) Science 275, 1800-1804] shows that major rearrangements of several active site side chains occur upon substrate binding.

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Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

November 24, 1998

Volume

37

Issue

47

Start / End Page

16601 / 16611

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Sesquiterpenes
  • Rats
  • Protein Structure, Tertiary
  • Protein Structure, Secondary
  • Polyisoprenyl Phosphates
  • Organophosphonates
  • Oligopeptides
  • Models, Molecular
  • Macromolecular Substances
 

Citation

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Strickland, C. L., Windsor, W. T., Syto, R., Wang, L., Bond, R., Wu, Z., … Weber, P. C. (1998). Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue. Biochemistry, 37(47), 16601–16611. https://doi.org/10.1021/bi981197z
Strickland, C. L., W. T. Windsor, R. Syto, L. Wang, R. Bond, Z. Wu, J. Schwartz, H. V. Le, L. S. Beese, and P. C. Weber. “Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.Biochemistry 37, no. 47 (November 24, 1998): 16601–11. https://doi.org/10.1021/bi981197z.
Strickland CL, Windsor WT, Syto R, Wang L, Bond R, Wu Z, et al. Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue. Biochemistry. 1998 Nov 24;37(47):16601–11.
Strickland, C. L., et al. “Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.Biochemistry, vol. 37, no. 47, Nov. 1998, pp. 16601–11. Pubmed, doi:10.1021/bi981197z.
Strickland CL, Windsor WT, Syto R, Wang L, Bond R, Wu Z, Schwartz J, Le HV, Beese LS, Weber PC. Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue. Biochemistry. 1998 Nov 24;37(47):16601–16611.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

November 24, 1998

Volume

37

Issue

47

Start / End Page

16601 / 16611

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Sesquiterpenes
  • Rats
  • Protein Structure, Tertiary
  • Protein Structure, Secondary
  • Polyisoprenyl Phosphates
  • Organophosphonates
  • Oligopeptides
  • Models, Molecular
  • Macromolecular Substances