General Information

Database accession: MF7000491

Name: TnmS3 protein with TNM C

PDB ID: 6bbx PDBe

Experimental method: X-ray (2.20 Å)

Assembly: Homodimer

Source organism: Streptomyces sp

Primary publication of the structure:

Chang CY, Yan X, Crnovcic I, Annaval T, Chang C, Nocek B, Rudolf JD, Yang D, Babnigg G, Joachimiak A, Phillips GN, Shen B
Resistance to Enediyne Antitumor Antibiotics by Sequestration.
(2018) Cell Chem Biol 25: 1075-1085.e4

PMID: 29937405 PubMed

Abstract:

The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers-apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar KD values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance.


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

Molecular function:

dioxygenase activity dioxygenase activity GeneOntology

metal ion binding metal ion binding GeneOntology

Biological process: not assigned

Cellular component: not assigned

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 2 distinct polypeptide molecules

Chains: A, B

Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.

Number of unique protein segments: 1


Chain A

Name: Glyoxalase/bleomycin resisance protein/dioxygenase

Source organism: Streptomyces sp

Length: 124 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMAISHVQLFSVPVSDQEKAKDFYVETVGFDLLADQPGVHGRWLQVAPKGADTSLVLVDWFPTMPPGSLRGLLLRTDDVDADCARLQERGVAVDGPKNTPWGRQAMFSDPDGNVIGLNQPSASAG

UniProtKB AC: A0A125SA29 (positions: 1-120) UniProt

Coverage: 96%

Chain B

Name: Glyoxalase/bleomycin resisance protein/dioxygenase

Source organism: Streptomyces sp

Length: 124 residues

Sequence:Sequence according to the corresponding UniProt protein segmentMAISHVQLFSVPVSDQEKAKDFYVETVGFDLLADQPGVHGRWLQVAPKGADTSLVLVDWFPTMPPGSLRGLLLRTDDVDADCARLQERGVAVDGPKNTPWGRQAMFSDPDGNVIGLNQPSASAG

UniProtKB AC: A0A125SA29 (positions: 1-120) UniProt

Coverage: 96%

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

Representative domain in related structures: Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily

Evidence level: Indirect evidence

Evidence coverage: The full structure participates in mutual synergistic folding.

Complex Evidence:

The VOC superfamily of metalloenzymes is characterized by a three-dimensional domain-swapped arrangement of tandem βαβββ-motifs (PMID:24447055). The original gene duplication event led to the βαβββ tandem structure, which appears to require dimerization for stability. Two different forms of domain-swapped dimers may coexist in solution (PMID:12121648) in which both subunits of the homodimer participate in coordination of each metal ion and formation of the U-shaped active sites in the enzyme (PMID:24004181). The complex is predominantly dimeric in solution (gel filtration) (PMID:12121648).

Chain A:

N/A

Chain B:

N/A

Surface and contacts features:

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 are 64 related structures in the MFIB database:






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