1d8d › Citations

The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures.

Long SB, Casey PJ, Beese LS
Structure 8 209-22 (2000)
Cited: 67 times
EuropePMC logo PMID: 10673434

Abstract

Background

The protein farnesyltransferase (FTase) catalyzes addition of the hydrophobic farnesyl isoprenoid to a cysteine residue fourth from the C terminus of several protein acceptors that are essential for cellular signal transduction such as Ras and Rho. This addition is necessary for the biological function of the modified proteins. The majority of Ras-related human cancers are associated with oncogenic variants of K-RasB, which is the highest affinity natural substrate of FTase. Inhibition of FTase causes regression of Ras-mediated tumors in animal models.

Results

We present four ternary complexes of rat FTase co-crystallized with farnesyl diphosphate analogs and K-Ras4B peptide substrates. The Ca(1)a(2)X portion of the peptide substrate binds in an extended conformation in the hydrophobic cavity of FTase and coordinates the active site zinc ion. These complexes offer the first view of the polybasic region of the K-Ras4B peptide substrate, which confers the major enhancement of affinity of this substrate. The polybasic region forms a type I beta turn and binds along the rim of the hydrophobic cavity. Removal of the catalytically essential zinc ion results in a dramatically different peptide conformation in which the Ca(1)a(2)X motif adopts a beta turn. A manganese ion binds to the diphosphate mimic of the farnesyl diphosphate analog.

Conclusion

These ternary complexes provide new insight into the molecular basis of peptide substrate specificity, and further define the roles of zinc and magnesium in the prenyltransferase reaction. Zinc is essential for productive Ca(1)a(2)X peptide binding, suggesting that the beta-turn conformation identified in previous nuclear magnetic resonance (NMR) studies reflects a state in which the cysteine is not coordinated to the zinc ion. The structural information presented here should facilitate structure-based design and optimization of inhibitors of Ca(1)a(2)X protein prenyltransferases.

Reviews - 1d8d mentioned but not cited (4)

  1. Protein prenylation: enzymes, therapeutics, and biotechnology applications. Palsuledesai CC, Distefano MD. ACS Chem Biol 10 51-62 (2015)
  2. Protein prenyltransferases. Maurer-Stroh S, Washietl S, Eisenhaber F. Genome Biol 4 212 (2003)
  3. Protein Prenyltransferases and Their Inhibitors: Structural and Functional Characterization. Marchwicka A, Kamińska D, Monirialamdari M, Błażewska KM, Gendaszewska-Darmach E. Int J Mol Sci 23 5424 (2022)
  4. Synthetic isoprenoid analogues for the study of prenylated proteins: Fluorescent imaging and proteomic applications. Wang YC, Distefano MD. Bioorg Chem 64 59-65 (2016)

Articles - 1d8d mentioned but not cited (16)

  1. Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies. Jiang H, Zhang X, Chen X, Aramsangtienchai P, Tong Z, Lin H. Chem Rev 118 919-988 (2018)
  2. Refinement and prediction of protein prenylation motifs. Maurer-Stroh S, Eisenhaber F. Genome Biol 6 R55 (2005)
  3. Database of traditional Chinese medicine and its application to studies of mechanism and to prescription validation. Chen X, Zhou H, Liu YB, Wang JF, Li H, Ung CY, Han LY, Cao ZW, Chen YZ. Br J Pharmacol 149 1092-1103 (2006)
  4. The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics. Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS. Proc Natl Acad Sci U S A 98 12948-12953 (2001)
  5. Evaluation of alkyne-modified isoprenoids as chemical reporters of protein prenylation. DeGraw AJ, Palsuledesai C, Ochocki JD, Dozier JK, Lenevich S, Rashidian M, Distefano MD. Chem Biol Drug Des 76 460-471 (2010)
  6. Context-dependent substrate recognition by protein farnesyltransferase. Hougland JL, Lamphear CL, Scott SA, Gibbs RA, Fierke CA. Biochemistry 48 1691-1701 (2009)
  7. Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras. Novotny CJ, Hamilton GL, McCormick F, Shokat KM. ACS Chem Biol 12 1956-1962 (2017)
  8. Discovering RNA-protein interactome by using chemical context profiling of the RNA-protein interface. Parisien M, Wang X, Perdrizet G, Lamphear C, Fierke CA, Maheshwari KC, Wilde MJ, Sosnick TR, Pan T. Cell Rep 3 1703-1713 (2013)
  9. Caged protein prenyltransferase substrates: tools for understanding protein prenylation. DeGraw AJ, Hast MA, Xu J, Mullen D, Beese LS, Barany G, Distefano MD. Chem Biol Drug Des 72 171-181 (2008)
  10. Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. Hast MA, Fletcher S, Cummings CG, Pusateri EE, Blaskovich MA, Rivas K, Gelb MH, Van Voorhis WC, Sebti SM, Hamilton AD, Beese LS. Chem Biol 16 181-192 (2009)
  11. Expansion of protein farnesyltransferase specificity using "tunable" active site interactions: development of bioengineered prenylation pathways. Hougland JL, Gangopadhyay SA, Fierke CA. J Biol Chem 287 38090-38100 (2012)
  12. Modeling of RAS complexes supports roles in cancer for less studied partners. Engin HB, Carlin D, Pratt D, Carter H. BMC Biophys 10 5 (2017)
  13. Chemoprotective effects of inositol hexaphosphate against cyclophosphamide-induced testicular damage in rats. Alkhalaf MI, Alansari WS, Alshubaily FA, Alnajeebi AM, Eskandrani AA, Tashkandi MA, Babteen NA. Sci Rep 10 12599 (2020)
  14. Quantitative Assessment of Chirality of Protein Secondary Structures and Phenylalanine Peptide Nanotubes. Sidorova A, Bystrov V, Lutsenko A, Shpigun D, Belova E, Likhachev I. Nanomaterials (Basel) 11 3299 (2021)
  15. Mechanistic insight into impact of phosphorylation on the enzymatic steps of farnesyltransferase. Pekel H, Guzel M, Sensoy O. Protein Sci 31 e4414 (2022)
  16. GC-MS profiling of Bacillus spp. metabolites with an in vitro biological activity assessment and computational analysis of their impact on epithelial glioblastoma cancer genes. Naveed M, Ishfaq H, Rehman SU, Javed A, Waseem M, Makhdoom SI, Aziz T, Alharbi M, Alshammari A, Alasmari AF. Front Chem 11 1287599 (2023)


Reviews citing this publication (8)

  1. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. Lane KT, Beese LS. J Lipid Res 47 681-699 (2006)
  2. The polybasic region of Ras and Rho family small GTPases: a regulator of protein interactions and membrane association and a site of nuclear localization signal sequences. Williams CL. Cell Signal 15 1071-1080 (2003)
  3. Therapeutic intervention based on protein prenylation and associated modifications. Gelb MH, Brunsveld L, Hrycyna CA, Michaelis S, Tamanoi F, Van Voorhis WC, Waldmann H. Nat Chem Biol 2 518-528 (2006)
  4. Understanding and exploiting protein prenyltransferases. Nguyen UT, Goody RS, Alexandrov K. Chembiochem 11 1194-1201 (2010)
  5. Unraveling the mechanism of the farnesyltransferase enzyme. Sousa SF, Fernandes PA, Ramos MJ. J Biol Inorg Chem 10 3-10 (2005)
  6. Structure, catalysis, and inhibition mechanism of prenyltransferase. Chang HY, Cheng TH, Wang AH. IUBMB Life 73 40-63 (2021)
  7. Module assembly for designing multivalent mid-sized inhibitors of protein-protein interactions. Ohkanda J. Chem Rec 13 561-575 (2013)
  8. The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function. Abdelkarim H, Banerjee A, Grudzien P, Leschinsky N, Abushaer M, Gaponenko V. Int J Mol Sci 20 E5718 (2019)

Articles citing this publication (39)

  1. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. Reid TS, Terry KL, Casey PJ, Beese LS. J Mol Biol 343 417-433 (2004)
  2. Reaction path of protein farnesyltransferase at atomic resolution. Long SB, Casey PJ, Beese LS. Nature 419 645-650 (2002)
  3. Structure of mammalian protein geranylgeranyltransferase type-I. Taylor JS, Reid TS, Terry KL, Casey PJ, Beese LS. EMBO J 22 5963-5974 (2003)
  4. Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach. Pang YP, Xu K, Yazal JE, Prendergas FG. Protein Sci 9 1857-1865 (2000)
  5. GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site. Lu S, Banerjee A, Jang H, Zhang J, Gaponenko V, Nussinov R. J Biol Chem 290 28887-28900 (2015)
  6. Efficient prenylation by a plant geranylgeranyltransferase-I requires a functional CaaL box motif and a proximal polybasic domain. Caldelari D, Sternberg H, Rodríguez-Concepción M, Gruissem W, Yalovsky S. Plant Physiol 126 1416-1429 (2001)
  7. GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase. Kuchay S, Wang H, Marzio A, Jain K, Homer H, Fehrenbacher N, Philips MR, Zheng N, Pagano M. Nat Struct Mol Biol 26 628-636 (2019)
  8. Structures of Cryptococcus neoformans protein farnesyltransferase reveal strategies for developing inhibitors that target fungal pathogens. Hast MA, Nichols CB, Armstrong SM, Kelly SM, Hellinga HW, Alspaugh JA, Beese LS. J Biol Chem 286 35149-35162 (2011)
  9. Flexible-body motions of calmodulin and the farnesylated hypervariable region yield a high-affinity interaction enabling K-Ras4B membrane extraction. Jang H, Banerjee A, Chavan T, Gaponenko V, Nussinov R. J Biol Chem 292 12544-12559 (2017)
  10. Zinc-promoted alkyl transfer: a new role for zinc. Penner-Hahn J. Curr Opin Chem Biol 11 166-171 (2007)
  11. The CaaX specificities of Arabidopsis protein prenyltransferases explain era1 and ggb phenotypes. Andrews M, Huizinga DH, Crowell DN. BMC Plant Biol 10 118 (2010)
  12. Efficient farnesylation of an extended C-terminal C(x)3X sequence motif expands the scope of the prenylated proteome. Blanden MJ, Suazo KF, Hildebrandt ER, Hardgrove DS, Patel M, Saunders WP, Distefano MD, Schmidt WK, Hougland JL. J Biol Chem 293 2770-2785 (2018)
  13. Structural analysis of DNA-PKcs: modelling of the repeat units and insights into the detailed molecular architecture. Brewerton SC, Doré AS, Drake AC, Leuther KK, Blundell TL. J Struct Biol 145 295-306 (2004)
  14. Molecular dynamics simulations on the critical states of the farnesyltransferase enzyme. Sousa SF, Fernandes PA, Ramos MJ. Bioorg Med Chem 17 3369-3378 (2009)
  15. Protein farnesyltransferase-catalyzed isoprenoid transfer to peptide depends on lipid size and shape, not hydrophobicity. Subramanian T, Liu S, Troutman JM, Andres DA, Spielmann HP. Chembiochem 9 2872-2882 (2008)
  16. Computational studies of the farnesyltransferase ternary complex part I: substrate binding. Cui G, Wang B, Merz KM. Biochemistry 44 16513-16523 (2005)
  17. Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design. Mabanglo MF, Hast MA, Lubock NB, Hellinga HW, Beese LS. Protein Sci 23 289-301 (2014)
  18. Theoretical studies on farnesyltransferase: the distances paradox explained. Sousa SF, Fernandes PA, Ramos MJ. Proteins 66 205-218 (2007)
  19. Engineering protein farnesyltransferase for enzymatic protein labeling applications. Dozier JK, Khatwani SL, Wollack JW, Wang YC, Schmidt-Dannert C, Distefano MD. Bioconjug Chem 25 1203-1212 (2014)
  20. Lysine beta311 of protein geranylgeranyltransferase type I partially replaces magnesium. Hartman HL, Bowers KE, Fierke CA. J Biol Chem 279 30546-30553 (2004)
  21. Coupling of isoprenoid triflates with organoboron nucleophiles: synthesis and biological evaluation of geranylgeranyl diphosphate analogues. Mu Y, Eubanks LM, Poulter CD, Gibbs RA. Bioorg Med Chem 10 1207-1219 (2002)
  22. Structure of protein geranylgeranyltransferase-I from the human pathogen Candida albicans complexed with a lipid substrate. Hast MA, Beese LS. J Biol Chem 283 31933-31940 (2008)
  23. Finding a needle in the haystack: computational modeling of Mg2+ binding in the active site of protein farnesyltransferase. Yang Y, Chakravorty DK, Merz KM. Biochemistry 49 9658-9666 (2010)
  24. The chaperone SmgGDS-607 has a dual role, both activating and inhibiting farnesylation of small GTPases. García-Torres D, Fierke CA. J Biol Chem 294 11793-11804 (2019)
  25. Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif. Sousa SF, Coimbra JT, Paramos D, Pinto R, Guimarães RS, Teixeira V, Fernandes PA, Ramos MJ. J Mol Model 19 673-688 (2013)
  26. The search for the mechanism of the reaction catalyzed by farnesyltransferase. Sousa SF, Fernandes PA, Ramos MJ. Chemistry 15 4243-4247 (2009)
  27. Lysine(164)alpha of protein farnesyltransferase is important for both CaaX substrate binding and catalysis. Hightower KE, De S, Weinbaum C, Spence RA, Casey PJ. Biochem J 360 625-631 (2001)
  28. Substituted imidazo[1,2-a]pyridines as β-strand peptidomimetics. Kang CW, Sun Y, Del Valle JR. Org Lett 14 6162-6165 (2012)
  29. Aromatic farnesyl diphosphate analogues: vinyl triflate-mediated synthesis and preliminary enzymatic evaluation. Zhou C, Shao Y, Gibbs RA. Bioorg Med Chem Lett 12 1417-1420 (2002)
  30. Identification of mono- and bisubstrate inhibitors of protein farnesyltransferase and inducers of apoptosis from a pepticinnamin E library. Thutewohl M, Kissau L, Popkirova B, Karaguni IM, Nowak T, Bate M, Kuhlmann J, Müller O, Waldmann H. Bioorg Med Chem 11 2617-2626 (2003)
  31. Breaking the singleton of germination protease. Pei J, Grishin NV. Protein Sci 11 691-697 (2002)
  32. Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. Ohkanda J, Strickland CL, Blaskovich MA, Carrico D, Lockman JW, Vogt A, Bucher CJ, Sun J, Qian Y, Knowles D, Pusateri EE, Sebti SM, Hamilton AD. Org Biomol Chem 4 482-492 (2006)
  33. Module assembly for protein-surface recognition: geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces. Machida S, Usuba K, Blaskovich MA, Yano A, Harada K, Sebti SM, Kato N, Ohkanda J. Chemistry 14 1392-1401 (2008)
  34. Synthesis and conformational analysis of bicyclic extended dipeptide surrogates. Ranatunga S, Liyanage W, Del Valle JR. J Org Chem 75 5113-5125 (2010)
  35. Protein farnesyltransferase: flexible docking studies on inhibitors using computational modeling. Guida WC, Hamilton AD, Crotty JW, Sebti SM. J Comput Aided Mol Des 19 871-885 (2005)
  36. Exploration of GGTase-I substrate requirements. Part 1: Synthesis and biochemical evaluation of novel aryl-modified geranylgeranyl diphosphate analogs. Temple KJ, Wright EN, Fierke CA, Gibbs RA. Bioorg Med Chem Lett 26 3499-3502 (2016)
  37. Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase. Wang Y, Xu F, Nichols CB, Shi Y, Hellinga HW, Alspaugh JA, Distefano MD, Beese LS. J Med Chem 65 13753-13770 (2022)
  38. Hydrophobicity and functionality maps of farnesyltransferase. Ahmed S, Majeux N, Caflisch A. J Mol Graph Model 19 307-17, 380-7 (2001)
  39. The dynamics of cholesterol molecules near the surface of protein farnesyltransferase - computer simulation. Raczyński P, Gburski Z. Biomol Eng 24 568-571 (2007)


Related citations provided by authors (2)

  1. Crystal Structure of Protein Farnesyltransferase at 2.25A Resolution. Park H-W, Boduluri SR, Moomaw JF, Casey PJ, Beese LS Science 275 1800-1804 (1997)
  2. Co-crystal Structure of Mammalian Protein Farnesyltransferase with a Farnesyl Diphosphate Substrate. Long SB, Casey PJ, Beese LS Biochemistry 37 9612-9618 (1998)

Quick links