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8kht

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The structure of Rv0097 with substrate

Structural highlights

8kht is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.05Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

INLPE_MYCTU Involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Catalyzes the conversion of (3R)-3-[(carboxymethyl)amino]fatty acids to (3R)-3-isocyanyl-fatty acids through an oxidative decarboxylation mechanism, thereby generating the isonitrile group of INLPs (By similarity).[UniProtKB:A0A3B6UEU3]^[1]

Publication Abstract from PubMed

A number of bacteria are known to produce isonitrile-containing peptides (INPs) that facilitate metal transport and are important for cell survival; however, considerable structural variation is observed among INPs depending on the producing organism. While non-heme iron 2-oxoglutarate dependent isonitrilases catalyze isonitrile formation, how the natural variation in INP structure is controlled and its implications for INP bioactivity remain open questions. Herein, total chemical synthesis is utilized with X-Ray crystallographic analysis of mycobacterial isonitrilases to provide a structural model of substrate specificity that explains the longer alkyl chains observed in mycobacterial versus Streptomyces INPs. Moreover, proton NMR titration experiments demonstrate that INPs regardless of alkyl chain length are specific for binding copper instead of zinc. These results suggest that isonitrilases may act as gatekeepers in modulating the observed biological distribution of INP structures and this distribution may be primarily related to differing metal transport requirements among the producing strains.

Variation in biosynthesis and metal-binding properties of isonitrile-containing peptides produced by Mycobacteria versus Streptomyces.,Chen TY, Chen J, Ruszczycky MW, Hilovsky D, Hostetler T, Liu X, Zhou J, Chang WC ACS Catal. 2024 Apr 5;14(7):4975-4983. doi: 10.1021/acscatal.4c00645. Epub 2024 , Mar 19. PMID:38895101^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Harris NC, Sato M, Herman NA, Twigg F, Cai W, Liu J, Zhu X, Downey J, Khalaf R, Martin J, Koshino H, Zhang W. Biosynthesis of isonitrile lipopeptides by conserved nonribosomal peptide synthetase gene clusters in Actinobacteria. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7025-7030. PMID:28634299 doi:10.1073/pnas.1705016114
↑ Chen TY, Chen J, Ruszczycky MW, Hilovsky D, Hostetler T, Liu X, Zhou J, Chang WC. Variation in biosynthesis and metal-binding properties of isonitrile-containing peptides produced by Mycobacteria versus Streptomyces. ACS Catal. 2024 Apr 5;14(7):4975-4983. PMID:38895101 doi:10.1021/acscatal.4c00645