Drugging tRNA aminoacylation

Figures & data

Scheme 1.  

Figure 1. Druggable regions for inhibition of aminoacylation. Examples of drugs targeting each region of either the aaRS enzyme of tRNA substrate are shown. Acceptor stem and anticodon tRNA regions (highlighted in red) are frequently strong determinants for aaRS recognition. Notable residues comprising the anticodon (N34, N35, N36), CCA-tail (A76, C75, C74) and discriminator base (N73) are also shown. AaRS regions involved in tRNA recognition are also depicted, including the tRNA, ATP, and amino acid sites in the catalytic domain, as well as the anticodon recognition region (shown in red) of the anticodon binding domain.

Table 1. Identity elements in E. coli tRNA vs human mitochondrial tRNA vs. human cytosolic tRNA.

Amino acid	E. coli	Human Mitochondria	Human cytosol	Reference
Leucine	A73	A73	A73	Breitschopf (1994) [50]
	U8.A14	U8.A14		Breitschopf (1995) [115]
Serine	G73	A73 (Ser1) or G73 (Ser2)		Achsel (1993) [51]
	C72	C72 (Ser1) or U72 (Ser2)		Breitschopf (1995) [115]
	G2:C71	A2:U71	A2:U71
	A3:U70	G3:C70 (Ser1) or A3:U70 (Ser2)	C11:G24
	C11:G24	Δ11:24 (Ser1) or A11:U24 (Ser2)
	R4:Y69	A4:U69
Proline	A73	A73		Stehlin (1998) [52]
	G72	G72
	G35, G36	G35, G36
	G15.C48	A15.U48	G15:C48
Glycine	U73	A73	A73	Hipps (1995) [53]
	G1:C72	A1:U72	G1:C72
	C2:G71	C2:G71
	G3:C70	U3:A70	G3:C70
	C35, C36	C35, C36
Phenylalanine	A73	A73		Nazarenko (1992) [54]
	G34	G34
	A35	A35
	A36	A36
	G27:C43	A27:U43	U27:A43
	G28:C42	U28.U42	U28:A42
	U20,	U20	G20
	G44	A44	A44
	U45	G45	G45
	U59	A59	U59
	U60	U60	C60
Alanine	A73	A73		Hou (1989) [116]
	G2:C71	A2:U71 or G2:C71
	G3.U70	G3:C70	G3:U70
	G4:C69	G4:C69
	G20	A20 or U20	D20(D= A, G, or U)

Table 1. E. coli tRNA identity elements shown to be divergent from human mitochondrial tRNA were further screened for divergence from human cytosolic tRNA identity elements. Conserved identity elements are shown in black. Identity elements in human mitochondrial or cytosolic tRNAs that diverge from those in E. coli are shown in blue. E. coli identity elements divergent from both human mitochondrial and cytosolic identity elements are shown in red. Identity elements in E. coli were determined biochemically as described by Giegé et al³⁷. Corresponding mitochondrial tRNA residues in H. sapien were identified using the mitotRNAdb database (http://trnadb.bioinf.uni-leipzig.de) [117]. Identity elements for H. sapien cytosolic tRNAs were determined biochemically, as detailed in the references provided. For positions where identity element positions identified in E. coli were not biochemically shown to affect aminoacylation in human cytosolic protein variants, the corresponding nucleotide at the homologous position is listed.

Figure 2. X-ray crystal structure of Neomycin B bound to tRNA^Phe. Shown at 2.6A° resolution (PDB file 1I9V), Neomycin B occupies a binding cleft on tRNA^Phe one full helical turn above the anticodon stem-loop. Interactions within 3.5 Å include nucleotides 20, 44, and 45, which are represented by dashed yellow lines.

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