General Information

Database Accession: DI4000001

Name: Cladosporin in complex with human lysyl-tRNA synthetase

PDB ID: 4ycu PDB

Experimental method: X-ray (2.10 Å)

Source organism: Homo sapiens

Proof of disorder: Confirmed

Kd: 3.30×10-06 M PubMed

Primary publication of the structure:

Fang, P., Han, H., Wang, J., Chen, K., Chen, X., Guo, M.
Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor
(2015) Chem. Biol. 22: 1-

PMID: 26074468 PubMed

Abstract:

Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits Plasmodium falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report three crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all three structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydropyran moiety of cladosporin are critical for the specificity of cladosporin against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure-driven drug development.


Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

protein binding Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules). GeneOntology

Biological process:

tRNA aminoacylation for protein translation The synthesis of aminoacyl tRNA by the formation of an ester bond between the 3'-hydroxyl group of the most 3' adenosine of the tRNA, to be used in ribosome-mediated polypeptide synthesis. GeneOntology

negative regulation of cell proliferation Any process that stops, prevents or reduces the rate or extent of cell proliferation. GeneOntology

positive regulation of protein modification process Any process that activates or increases the frequency, rate or extent of the covalent alteration of one or more amino acid residues within a protein. GeneOntology

Cellular component:

nucleus A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent. GeneOntology

cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes. GeneOntology

membrane A lipid bilayer along with all the proteins and protein complexes embedded in it an attached to it. GeneOntology

aminoacyl-tRNA synthetase multienzyme complex A multienzyme complex found in all multicellular eukaryotes composed of eight proteins with aminoacyl-tRNA synthetase activities (abbreviated as: ArgRS, AspRS, GluProRS, GlnRS, IleRS, LeuRS, LysRS, MetRS where RS is the enzyme, preceded by the amino acid it uses as a substrate) as well as three non-synthetase proteins (p43, p38, and p18) with diverse functions. Several of these subunits are known dimers, so the total polypeptide count in the multisynthetase complex is at least fifteen. All of the enzymes in this assembly catalyze the same reaction, the covalent attachment of an amino acid to either the 2'- or 3'-hydroxyl of the 3'-terminal adenosine of tRNA, but using different substrates. GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 5 distinct polypeptide molecules

Chains: C, A, B, D, E

Notes: Chains D and E were generated using the biomatrices described in the PDB file.

Chain C

Name: Aminoacyl tRNA synthase complex-interacting multifunctional protein 2 Disordered Confirmed

Source organism: Homo sapiens

Length: 36 residues

Sequence:Sequence according to PDB SEQRESMPMYQVKPYHGGGAPLRVELPTCMYRLPNVHGRSYG

UniProtKB AC: Q13155 (positions: 1-36) UniProt Coverage: 11.3%

UniRef90 AC: UniRef90_Q13155 (positions: 1-36) UniRef90

Chain A

Name: Lysine--tRNA ligase Ordered component

Source organism: Homo sapiens

Length: 505 residues

Sequence:Sequence according to PDB SEQRESDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDHLTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGDIIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFVRQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAPELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSGMVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETRKILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKEGLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYGLPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPE

UniProtKB AC: Q15046 (positions: 72-576) UniProt Coverage: 84.6%

UniRef90 AC: UniRef90_Q15046 (positions: 72-576) UniRef90

Chain B

Name: Lysine--tRNA ligase Ordered component

Source organism: Homo sapiens

Length: 505 residues

Sequence:Sequence according to PDB SEQRESDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDHLTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGDIIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFVRQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAPELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSGMVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETRKILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKEGLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYGLPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPE

UniProtKB AC: Q15046 (positions: 72-576) UniProt Coverage: 84.6%

UniRef90 AC: UniRef90_Q15046 (positions: 72-576) UniRef90

Chain D

Name: Lysine--tRNA ligase Ordered component

Source organism: Homo sapiens

Length: 505 residues

Sequence:Sequence according to PDB SEQRESDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDHLTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGDIIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFVRQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAPELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSGMVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETRKILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKEGLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYGLPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPE

UniProtKB AC: Q15046 (positions: 72-576) UniProt Coverage: 84.6%

UniRef90 AC: UniRef90_Q15046 (positions: 72-576) UniRef90

Chain E

Name: Lysine--tRNA ligase Ordered component

Source organism: Homo sapiens

Length: 505 residues

Sequence:Sequence according to PDB SEQRESDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDHLTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGDIIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFVRQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAPELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSGMVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETRKILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKEGLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYGLPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPE

UniProtKB AC: Q15046 (positions: 72-576) UniProt Coverage: 84.6%

UniRef90 AC: UniRef90_Q15046 (positions: 72-576) UniRef90

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Chain C: Disordered Confirmed

The interacting region of the protein has been shown to be highly flexible corresponding to missing coordinates in X-ray structures (PDB ID: 4ycw). The protein region involved in the interaction contains two related conserved motifs (motif 1 and 2) linked by a natural Gly linker and a conserved sequence that makes a 180 degree turn (PMID: 23159739).

Chain A: Ordered component

tRNA synthetase domain involved in the interaction is known to adopt a stable structure in isolation in tetrameric form (see Pfam domain PF00152). A solved structure of the domain tetramer without bound ligands is represented by PDB ID 3bju.

Chain B: Ordered component

tRNA synthetase domain involved in the interaction is known to adopt a stable structure in isolation in tetrameric form (see Pfam domain PF00152). A solved structure of the domain tetramer without bound ligands is represented by PDB ID 3bju.

Chain D: Ordered component

tRNA synthetase domain involved in the interaction is known to adopt a stable structure in isolation in tetrameric form (see Pfam domain PF00152). A solved structure of the domain tetramer without bound ligands is represented by PDB ID 3bju.

Chain E: Ordered component

tRNA synthetase domain involved in the interaction is known to adopt a stable structure in isolation in tetrameric form (see Pfam domain PF00152). A solved structure of the domain tetramer without bound ligands is represented by PDB ID 3bju.

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

There is 1 related structure in the Protein Data Bank:



Domain Type:

tRNA synthetase







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