Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review
Abstract
:1. Introduction
2. Crystal Structures of 5-FU Complexes in the Protein Data Bank (PDB)
3. The Binding Mode of 5-FU
3.1. Dihydropyrimidine Dehydrogenase
3.2. Uracil Phosphoribosyltransferase
3.3. RNA-Dependent RNA Polymerase
3.4. Uridine Phosphorylase
3.5. rRNA N-Glycosidase
3.6. Uracil-DNA Glycosylase
3.7. Pyrimidine Operon Regulatory Protein PyrR
3.8. PI3Kα
3.9. Dihydropyrimidinase
3.10. Dihydroorotases
3.11. Single-Stranded DNA-Binding Proteins SsbA and SsbB
3.12. Hydroxydechloroatrazine Ethylaminohydrolase VCZ
4. Interaction Patterns
- Type 1 (P-R type): The contact distance involves residues from both P (Arg and Lys) and R (Phe, Tyr, Trp, and His) types.
- Type 2 (P type): The contact distance involves more than two P-type residues, Arg and/or Lys.
- Type 3 (R type): The contact distance involves R-type residues, Phe, Tyr, Trp, and/or His.
Type | PDB | Interactive Residues | HB | WB | π-π Int. | F5 (HB) | F5 (CD) | N1 or N3 (HB) | N1 or N3 (CD) | N3 (HB) | N3 (CD) | O4 (HB) | O4 (CD) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 3NBQ | R94, T141, S142, G143, F213, Q217, R219, I247, E248, M249, L272, L273, I281, W1-R94(B) | T141, G143, Q217, R219 | W1-R94(B) | - | G143 [N] | I281, L272, L273 | T141 [OG1], Q217 [OE1], R219 [NH1] | F213 | Q217 [OE1], R219 [NH1] | F213 | R219 [NH1] [NH2] | - |
1 | 4O0O | V69, Y70, G109, N110, Y111, I155, R163 | V69, G109, Y111, R163 | - | - | V69 [O], R163 [NH1], R163 [NH2] | I155,Y70 | G109 [O] | - | G109 [O] | - | - | - |
1 | 5IAO | R58, D120, V176, H177, R179, W4-V178 | R58, H177, R179, | W4-V178 | - | R58 [NH1], R58 [NE2] | D120 | H177 [ND1] | - | H177 [ND1] | - | R58 [NH1] | D120 |
1 | 6KLK | H61, L64, F66, Kcx150, F152, Y155, H183, M288, S289, D316, C318, N337, G338, | Kcx150, S289, D316, C318, N337, G338, | - | - | Kcx150 [OQ2] | F152 | S289 [O], N337 [O] | Y155, H183 | N337 [O] | C318 [SG] | H61, L64 | |
1 | 6L0B | H16, R18, N43, Kcx98, T105, T106, H137, K230, D258, A260, H262, G276, A275 | H16, R18, N43, T105 | - | H16 (4.9Å) | A275 [O] | H262 | T105 [OG1], H16 [ND1] | - | H16 [ND1] | - | R18 [NH1], N43 [ND2] | - |
1 | 7DEP | T12, K13, T30, F48, N50 | T12, K13, T30, N50 | - | - | N50 [ND2] | - | T12 [OG1], | - | T12 [OG1], | - | T12 [OG1], K13 [NZ], T30 [OG1] | - |
1 | 7YM1 | R18, P21, F54, V52, Q78, R80, E94, V96 | R18, R80 | - | - | Q78, F54 | R18 [NH2] | V52, V96 | R18 [NH2] | - | - | P21 | |
1 | 8GVZ | R1475, H1473, N1505, Kcx1556, T1562, F1563, H1590, R1661, D1686, A1688, H1690, P1702, | R1475, H1473, N1505, T1562, H1590 | W1- T1562 | H1473 (4.5 Å) | R1475 [NH2] | F1360, H1690 | T1562 [OG1], H1473 [ND1] | - | H1473 [ND1] | - | R1475 [NH1] [NH2], N1505 [ND2] | - |
2 | 3NAI | R185, D245, R395, D346, D347 | R185, D245, R395 | - | - | R185 [NH1], R185 [NH2], R395 [NH2] | - | D346 [OD2] | - | D346 [OD2] | - | - | - |
2 | 5SXC | E620, K621, K656 | K656 | - | - | K656 [NZ] | - | - | E620 | - | - | K656 [NZ] | - |
3 | 1H7X | N609, E611, L612, I613, N668, S670, N736, T737, W2-G764 | N609, N668, S670, N736, T737 | W2-G764 | - | - | L612, I613, FMN | N609 [OD1], N736 [OD1] | - | N609 [OD1], N736 [OD1] | - | N668 [ND2], S670 [OG], N736 [ND2] | - |
3 | 1UPF | M166, A168, Y227, Y228, I229, G234, F236, D316 | Y227, I229, G234, F236 | - | - | Y227 [O], I229 [N] | A168 | G234 [O] | - | G234 [O] | - | I229 [N] | - |
3 | 4WRY | G66, Q67, D68, Y70, S80, F81, S93, N127, H191, W2-L79 | G66, Q67, D68, Y70, S93, N127, H191 | W2-L79 | Y70 (4.7 Å) F81 (3.9 Å) | S93 [OG] | - | Y70 [N], N127 [OD1] | - | N127 [OD1] | - | Q67 [N], D68 [N], H191 [NE2] | - |
3 | 8IS4 | H70, Q73, W90, Y130, C207, E237, L300, D322, W3-S326 | Q73, Y130, C207, E237 | W3-S326 | H234 (4.7 Å) | C207 [SG], Y130 [OH] | - | - | - | - | - | Q73 [NE2], Y130 [OH] | W90 [CH2] H70 [NE2] |
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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PDB ID | Organism | Crystal Structure | Unique Ligand |
---|---|---|---|
1H7X | Sus scrofa | Dihydropyrimidine dehydrogenase (DPD) from pig, ternary complex of a mutant enzyme (C671A), NADPH and 5-fluorouracil | FAD, FMN, NDP, SF4, URF |
1RXC | Escherichia coli (strain K12) | E. coli uridine phosphorylase: 5-fluorouracil ribose-1-phosphate complex | 5UD, K, PO4, R1P, URF |
1UPF | Toxoplasma gondii | Structure of the uracil phosphoribosyltransferase, mutant C128V bound to the drug 5-fluorouracil | SO4, URF |
3KVR | Bos taurus | Trapping of an oxocarbenium ion intermediate in UP crystals | R2G, SO4, URF |
3KVV | Escherichia coli (strain K12) | Trapping of an oxocarbenium ion intermediate in UP crystals | R2B, SO4, URF |
3NAI | Murine norovirus 1 | Crystal structures and functional analysis of murine norovirus RNA-dependent RNA polymerase | GOL, MG, MN3, SO4, URF |
3NBQ | Homo sapiens | Human uridine phosphorylase 1 (hUPP1) with 5-fluorouracil | URF |
4E1V | Salmonella typhimurium | X-RAY structure of the uridine phosphorylase from Salmonella typhimurium in complex with 5-fluorouracil at 2.15 Å resolution | EDO, GOL, K, URF |
4O0O | Momordica balsamina | Crystal structure of the complex of type 1 ribosome inactivating protein from Momordica balsamina with 5-fluorouracil at 2.59 Å resolution | GOL, NAG, URF |
4TXN | Schistosoma mansoni | Crystal structure of uridine phosphorylase from Schistosoma mansoni in complex with 5-fluorouracil | SO4, URF |
4WRY | Mycobacterium tuberculosis | Crystal structure of Mycobacterium tuberculosis uracil-DNA glycosylase in complex with 5-fluorouracil (B), Form I | CIT, CL, URF |
4WRZ | Mycobacterium tuberculosis | Crystal structure of Mycobacterium tuberculosis uracil-DNA glycosylase in complex with 5-fluorouracil (AB), Form I | CIT, CL, IPA, URF |
4WS0 | Mycobacterium tuberculosis | Crystal structure of Mycobacterium tuberculosis uracil-DNA glycosylase in complex with 5-fluorouracil (A), Form II | CL, EDO, URF |
4WS1 | Mycobacterium tuberculosis | Crystal structure of Mycobacterium tuberculosis uracil-DNA glycosylase in complex with 5-fluorouracil (AB), Form II | CL, EDO, URF |
5IAO | Mycobacterium tuberculosis | Structure and mapping of spontaneous mutational sites of PyrR from Mycobacterium tuberculosis | URF |
5SXC | Homo sapiens | Crystal structure of PI3Kalpha in complex with fragment 8 | SEP, URF |
6KLK | Pseudomonas aeruginosa | Crystal structure of the Pseudomonas aeruginosa dihydropyrimidinase complexed with 5-FU | KCX, URF, ZN |
6L0B | Saccharomyces cerevisiae | Crystal structure of dihydroorotase in complex with fluorouracil from Saccharomyces cerevisiae | KCX, URF, ZN |
7D8J | Staphylococcus aureus | S. aureus SsbB with 5-FU | URF |
7DEP | Staphylococcus aureus | S. aureus SsbB with 5-FU | URF |
7YM1 | Staphylococcus aureus | Structure of SsbA protein in complex with the anticancer drug 5-fluorouracil | GOL, URF |
8GVZ | Homo sapiens | Crystal structure of the human dihydroorotase domain in complex with the anticancer drug 5-fluorouracil | KCX, URF, ZN |
8IS4 | Obesumbacterium proteus | Structure of an isocytosine specific deaminase VCZ in complex with 5-FU | GOL, TRS, URF, ZN |
Molecule | Type of Binding Site | Area * | Volume * | Dimensions (x, y) of the Cavity (Å) # |
---|---|---|---|---|
Dihydropyrimidine dehydrogenase | 59.2 | 23.12 | 4.8, 7.1 | |
Uridine phosphorylase | 138.5 | 83.4 | 2.8, 6.7 | |
Uracil phosphoribosyltransferase | 566 | 710 | 11.5, 8.7 | |
RNA-dependent RNA polymerase | 2976 | 4400 | 17.3, 5.3 | |
PyrR | Surface | ND | ND | ND |
Phosphatidylinositol 4,5-bisphosphate 3-kinase | Surface | ND | ND | ND |
rRNA N-glycosidase | 82.6 | 39.4 | 11.7, 4.7 | |
Uracil-DNA glycosylase | 278.9 | 169.9 | 3.7, 4.3 | |
Dihydropyrimidinase | 132.6 | 45.9 | 4.1, 4.3 | |
Dihydroorotase (yeast) | 144.0 | 44.8 | 6.4, 5.4 | |
SsbB | 31.1 | 8.8 | 5.3, 8.6 | |
SsbA | 369 | 452 | 7.1, 5.3 | |
Dihydroorotase (human) | 289.7 | 213.4 | 6.9, 6.3 | |
Hydroxydechloroatrazine ethylaminohydrolase | 544 | 437 | 8.7, 11.4 |
Hydrogen Bond | The Contact Distance within <4 Å | ||||
---|---|---|---|---|---|
5-FU | Dist. [Å] | Residue | 5-FU | Dist. [Å] | Residue |
Type 1 (P-R type) | |||||
1.1 Uridine phosphorylase from Homo sapiens (3NBQ) | |||||
5FU [N1] | 4.1 | T141 [OG1] # | 5FU [O2] | 3.6 | E248 [CA] |
5FU [N1]/W1 | 3.8/4.0 | R94 [NH2] # | 5FU [O2] | 3.6 | M249 [CG] |
5FU [O2] | 2.9 | Q217 [NE2] | 5FU [C2] | 3.8 | I247 [O] |
5FU [N3] | 2.7 | Q217 [OE1] | 5FU [N3] | 3.4 | F231 [CE1] |
5FU [N3] | 4.0 | R219 [NH1] | 5FU [F5] | 3.7 | L272 [CD1] |
5FU [O4] | 2.9 | R219 [NH2] | 5FU [F5] | 3.5 | L273 [CD2] |
5FU [O4] | 3.2 | R219 [NH1] * | 5FU [F5] | 3.5 | I281 [CD1] |
5FU [F5] | 3.8 | G143 [N] # | |||
1.2 rRNA N-glycosidase from Momordica balsamina (4O0O) | |||||
5FU [O2] | 3.6 | Y111 [N] | 5FU [O2] | 4.0 | N110 [O2] |
5FU [N3] | 3.1 | G109 [O] | |||
5FU [F5] | 3.9 | V69 [O] | |||
5FU [F5] | 3.8 | R163 [NH1] * | |||
5FU [F5] | 3.5 | R163 [NH2] * | |||
1.3 PyrR from Mycobacterium tuberculosis (5IAO) | |||||
5FU [O2] | 2.7 | H177 [ND1] | 5FU [O4] | 4.0 | D120 [O4] |
5FU [O2] | 3.4 | R179 [NH2] # | |||
5FU [N3] | 3.0 | H177 [ND1] # | |||
5FU [O4] | 3.0 | R58 [NH1] | |||
5FU [O4]/W4 | 2.3/3.8 | V176 [O] # | |||
5FU [O4]/W4 | 2.3/2.8 | V178 [N] # | |||
5FU [F5] | 3.2 | R58 [NH1] * | |||
1.4 Dihydropyrimidinase from Pseudomonas aeruginosa (6KLK) | |||||
5FU [N1] | 3.1 | S289 [O] # | 5FU [N1] | 2.8 | Y155 [OH] |
5FU [O2] | 3.0 | S289 [N] * | 5FU [N1] | 4.0 | H183 [CE1] |
5FU [N3] | 3.2 | N337 [O] # | 5FU [O2] | 3.5 | M166 [CB] |
5FU [O4] | 2.9 | C318 [SG] * | 5FU [O2] | 3.9 | G338 [N] |
5FU [F5] | 3.4 | Kcx150 [OQ2] * | 5FU [C2] | 3.8 | D316 [OD2] |
5FU [O2] | 3.5 | H61 [CD2] | |||
5FU [O2] | 3.5 | L64 [CD2] | |||
5FU [C4] | 3.8 | F66 [CE2] | |||
5FU [F5] | 3.5 | F152 [CE1] | |||
1.5 Dihydroorotase from Saccharomyces cerevisiae (6L0B) | |||||
5FU [N1] | 3.3 | T105 [OG1] # | 5FU [O2] | 3.7 | Kcx98 [OQ2] |
5FU [N3] | 3.2 | H16 [ND1] | 5FU [O2] | 3.8 | H137 [ND1] |
5FU [O4] | 2.7 | R18 [NH1] | 5FU [O2] | 3.9 | K230 [O] |
5FU [O4] | 2.8 | N43 [ND2] | 5FU [O2] | 3.7 | D258 [OD2] |
5FU [F5] | 2.8 | R18 [NH2] | 5FU [F5] | 2.7 | T106 [OG] |
5FU [F5] | 2.9 | A275 [O] * | 5FU [F5] | 2.6 | H162 [NE2] |
5FU [C6] | 3.5 | A260 [CB] | |||
5FU [C6] | 3.8 | G276 [CA] | |||
1.6 SsbB from Staphylococcus aureus (7DEP) | |||||
5FU [N3] | 3.9 | T12 [OG1] # | 5FU [O2] | 3.9 | F48 [CD2] |
5FU [O4] | 3.9 | T12 [OG1] # | |||
5FU [O4] | 3.5 | K13 [NZ] | |||
5FU [O4] | 3.2 | T30 [OG1] * | |||
5FU [F5] | 3.3 | N50 [ND2] * | |||
1.7 SsbA from Staphylococcus aureus (7YM1) | |||||
5FU [O2] | 3.5 | R18 [NH1] # | 5FU [N1] | 3.5 | V52 [CG1] |
5FU [O2] | 3.7 | R80 [NH2] # | 5FU [N1] | 4.0 | V96 [CG1] |
5FU [O2] | 3.3 | R80 [NE] | 5FU [O2] | 2.7 | E94 [OE1] |
5FU [N3] | 2.5 | R18 [NH2] | 5FU [O4] | 4.0 | P21 [CD] |
5FU [F5] | 3.7 | F54 [CZ] | |||
5FU [F5] | 4.0 | Q78 [NE2] | |||
1.8 Dihydroorotase from Homo sapiens (8GVZ) | |||||
5FU [N1] | 2.9 | T1562 [OG1] # | 5FU [O2] | 3.8 | K1556 [OQ1] |
5FU [N1]/W1 | 3.9/2.8 | T1562 [OG1] # | 5FU [O2] | 4.1 | R1661 [O] |
5FU [O2] | 3.9 | H1590 [ND1] | 5FU [O2] | 3.7 | D1686 [OD2] |
5FU [O2]/W1 | 3.9/4.0 | T1562 [OG1] # | 5FU [C4] | 4.0 | A1688 |
5FU [N3] | 3.9 | H1473 [ND1] # | 5FU [F5] | 3.0 | F1563 [CD2] |
5FU [O4] | 2.6 | R1475 [NH1] | 5FU [F5] | 2.6 | H1690 [CE1] |
5FU [O4] | 3.4 | R1475 [NH2] # | 5FU [C6] | 2.8 | P1702 [O] |
5FU [O4] | 2.8 | N1505 [ND2] | |||
5FU [F5] | 2.6 | R1475 [NH2] * | |||
Type 2 (P type) | |||||
2.1 RNA-dependent RNA polymerase from murine norovirus 1 (3NAI) | |||||
5FU [N3] | 2.4 | D346 [OD2] * | 5FU [O2] | 3.2 | D245 [OD11] |
5FU [O4] | 4.0 | R185 [NH1] # | 5FU [O2] | 2.6 | D347 [OD2] |
5FU [F5] | 3.7 | R185 [NH1] * | |||
5FU [F5] | 3.6 | R185 [NH2] | |||
5FU [F5] | 3.4 | R395 [NH2] * | |||
2.2 Phosphatidylinositol 4,5-bisphosphate 3-kinase from Homo sapiens (5SXC) | |||||
5FU [O4] | 3.6 | K656 [NZ] | 5FU [N1] | 4.0 | E620 [O] |
5FU [F5] | 3.7 | K656 [NZ] * | 5FU [O2] | 3.0 | K621 [O] |
Type 3 (R type) | |||||
3.1 Dihydropyrimidine dehydrogenase from Sus scrofa (1H7X) | |||||
5FU [N1] | 2.9 | N609 [OD1] | 5FU [F5] | 3.6 | L162 [C] |
5FU [O2] | 2.9 | N609 [ND2] | 5FU [F5] | 3.8 | I163 [CG2] |
5FU [O2] | 2.9 | T737 [OG1] | 5FU [C6] | 3.0 | E611 [O] |
5FU [O2]/W2 | 3.5/3.2 | G764 [N] # | |||
5FU [N3] | 3.0 | N736 [OD1] | |||
5FU [O4] | 3.1 | N668 [ND2] | |||
5FU [O4] | 3.3 | S670 [OG] | |||
5FU [O4] | 3.0 | N736 [ND2] | |||
3.2 Uracil phosphoribosyltransferase from Toxoplasma gondii (1UPF) | |||||
5FU [O2] | 3.6 | F236 [N] | 5FU [O2] | 3.2 | D235 [OD1] |
5FU [N3] | 3.2 | G234 [O] | 5FU [N3] | 3.8 | M166 [CG] |
5FU [O4] | 3.4 | I229 [N] | 5FU [C4] | 3.8 | T228 [CD2] |
5FU [F5] | 3.8 | I229 [N] * | 5FU [F5] | 3.1 | A168 [CB] |
5FU [F5] | 3.0 | Y227 [O] | |||
3.3 Uracil-DNA glycosylase from Mycobacterium tuberculosis (4WRY) | |||||
5FU [N1] | 3.6 | Y70 [N] | 5FU [O2] | 3.3 | S80 [CA] |
5FU [O2] | 2.9 | N127 [ND2] | |||
5FU [O2] | 2.8 | F81 [N] | |||
5FU [O2]/W2 | 2.6/4.1 | L79 [O] # | |||
5FU [N3] | 2.8 | N127 [OD1] | |||
5FU [O4] | 2.8 | Q67 [N] | |||
5FU [O4] | 3.8 | D68 [N] | |||
5FU [O4] | 2.8 | H191 [NE2] * | |||
5FU [F5] | 3.9 | S93 [OG] * | |||
3.4 Hydroxydechloroatrazine ethylaminohydrolase from Obesumbacterium proteus (8IS4) | |||||
5FU [N1] | 3.4 | E237 [OE1] | 5FU [O2] | 3.0 | L300 [CD1] |
5FU [N3]/W3 | 3.1/4.0 | D322 [OG1] # | 5FU [O4] | 3.8 | W90 [CH2] |
5FU [N3]/W3 | 3.1/2.7 | S326 [OG] # | 5FU [O4] | 3.3 | H70 [NE2] |
5FU [O4] | 3.3 | Q73 [NE2] | |||
5FU [O4] | 2.7 | Y130 [OH] | |||
5FU [F5] | 3.1 | Y130 [OH] | |||
5FU [F5] | 3.8 | C207 [SG] * |
PDB ID | Organism | Length | Identities (%) | Positives (%) |
---|---|---|---|---|
3NBQ | Homo sapiens | 310 | 100 | 100 |
4TXN | Schistosoma mansoni | 296 | 44 | 64 |
1RXC | Escherichia coli (strain K12) | 253 | 32 | 46 |
4ETV | Salmonella typhimurium | 253 | 27 | 41 |
Binding Type | Number | Frequency (%) | F5 | N1 or N3 | N3 | O4 | N1, N3, or F5 | N3, O4, or F5 | Binding Pocket | One Dimension < 11 Å | One Dimension < 12 Å |
---|---|---|---|---|---|---|---|---|---|---|---|
Type 1 (P-R type) | 8 | 8/14 (57.1%) | 6/8 (75%) | 6/8 (75%) | 5/8 (35.7%) | 6/8 (75%) | 7/8 (87.5%) | 8/8 (100%) | 7/8 (87.5%) | 7/8 (87.5%) | 8/8 (100%) |
Type 2 (P type) | 2 | 2/14 (14.3%) | 2/2 (100%) | 0/2 (0%) | 0/2 (0%) | 1/2 (50%) | 2/2 (100%) | 2/2 (100%) | 1/2 (50%) | 1/2 (50%) | 1/2 (50%) |
Type 3 (R type) | 4 | 4/14 (28.6%) | 3/4 (75%) | 1/4 (25%) | 0/4 (0%) | 2/4 (50%) | 4/4 (100%) | 4/4 (100%) | 4/4 (100%) | 2/4 (50%) | 4/4 (100%) |
Total | 14 | 14/14 (100%) | 11/14 (78.6%) | 7/14 (50%) | 5/14 (35.7%) | 9/14 (64.3%) | 13/14 (92.9%) | 14/14 (100%) | 12/14 (85.7%) | 9/14 (64.3%) | 13/14 (92.9%) |
Type | PDB ID | Metal Ion | Interaction |
---|---|---|---|
1 | 6KLK | Zn | ZNα-F5 (3.6 Å) |
1 | 6L0B | Zn | Znα-O2 (3.0 Å), Znβ-O2 (2.4 Å) |
1 | 8GVZ | Zn | Znα-O2 (3.2 Å), Znβ-O2 (2.7 Å) |
2 | 3NAI | Mg | Mg-N3 (3.0 Å) |
3 | 8IS4 | Zn | Znα-N3 (3.0 Å) |
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Lin, E.-S.; Huang, C.-Y. Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review. Int. J. Mol. Sci. 2024, 25, 3404. https://doi.org/10.3390/ijms25063404
Lin E-S, Huang C-Y. Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review. International Journal of Molecular Sciences. 2024; 25(6):3404. https://doi.org/10.3390/ijms25063404
Chicago/Turabian StyleLin, En-Shyh, and Cheng-Yang Huang. 2024. "Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review" International Journal of Molecular Sciences 25, no. 6: 3404. https://doi.org/10.3390/ijms25063404
APA StyleLin, E. -S., & Huang, C. -Y. (2024). Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review. International Journal of Molecular Sciences, 25(6), 3404. https://doi.org/10.3390/ijms25063404