Database accession: MF7000648
Name: OxaC with SAH and oxaline
PDB ID: 5w7r
Experimental method: X-ray (2.50 Å)
Assembly: Homodimer
Source organism: Penicillium oxalicum
Primary publication of the structure:
Newmister SA, Romminger S, Schmidt JJ, Williams RM, Smith JL, Berlinck RGS, Sherman DH
Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway.
(2018) Org. Biomol. Chem. 16: 6450-6459
PMID: 30141817
Abstract:
Antimicrobial and anti-proliferative meleagrin and oxaline are roquefortine C-derived alkaloids produced by fungi of the genus Penicillium. Tandem O-methylations complete the biosynthesis of oxaline from glandicoline B through meleagrin. Currently, little is known about the role of these methylation patterns in the bioactivity profile of meleagrin and oxaline. To establish the structural and mechanistic basis of methylation in these pathways, crystal structures were determined for two late-stage methyltransferases in the oxaline and meleagrin gene clusters from Penicillium oxalicum and Penicillium chrysogenum. The homologous enzymes OxaG and RoqN were shown to catalyze penultimate hydroxylamine O-methylation to generate meleagrin in vitro. Crystal structures of these enzymes in the presence of methyl donor S-adenosylmethionine revealed an open active site, which lacks an apparent base indicating that catalysis is driven by proximity effects. OxaC was shown to methylate meleagrin to form oxaline in vitro, the terminal pathway product. Crystal structures of OxaC in a pseudo-Michaelis complex containing sinefungin and meleagrin, and in a product complex containing S-adenosyl-homocysteine and oxaline, reveal key active site residues with His313 serving as a base that is activated by Glu369. These data provide structural insights into the enzymatic methylation of these alkaloids that include a rare hydroxylamine oxygen acceptor, and can be used to guide future efforts towards selective derivatization and structural diversification and establishing the role of methylation in bioactivity.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
O-methyltransferase activity O-methyltransferase activity
Biological process:
heterocycle biosynthetic process obsolete heterocycle biosynthetic process
methylation methylation
organic cyclic compound biosynthetic process obsolete organic cyclic compound biosynthetic process
secondary metabolite biosynthetic process secondary metabolite biosynthetic process
Cellular component: not assigned
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, A-2
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: OxaC
Source organism: Penicillium oxalicum
Length: 405 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMTFSNADAQKIAVQKDVDEVVAAAQRFLHGSGNATSDEAKVDLQKKASNLVQTIRGPIPAALSSMEDIVKVASLRTLFEAGVFHAMPKGGASMTASEISAQTGLDKGILIRLMRAVTPLGPFHEVGEEEYAHTPFSEAYLTADIAGCFPVMSNFIFGPVLQICDFLRQNNWKDAITTRNNPFTLAHNCPGETMFEHLYKNSKNVAPVTKAEAADVDQIAMDLYPWEERLSDAKGSNATLVDIAGSHGNGTRAIMALAPKLNGCRFIVQDLEPVIGEHSQALRAEGIEPQVYDFLKQEQPVHGASIYYFRRVFHDWPDLPEGKKILDNTRAAMSREHSRILIHDIIVPEIGATMSHAWQDLSLMAIGGMERTEKDFARLLDIAGLALVKVWRKPGDMMGIIEARLK
UniProtKB AC: A0A1B2TT09 (positions: 8-405)
Coverage: 98%
Name: OxaC
Source organism: Penicillium oxalicum
Length: 405 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMTFSNADAQKIAVQKDVDEVVAAAQRFLHGSGNATSDEAKVDLQKKASNLVQTIRGPIPAALSSMEDIVKVASLRTLFEAGVFHAMPKGGASMTASEISAQTGLDKGILIRLMRAVTPLGPFHEVGEEEYAHTPFSEAYLTADIAGCFPVMSNFIFGPVLQICDFLRQNNWKDAITTRNNPFTLAHNCPGETMFEHLYKNSKNVAPVTKAEAADVDQIAMDLYPWEERLSDAKGSNATLVDIAGSHGNGTRAIMALAPKLNGCRFIVQDLEPVIGEHSQALRAEGIEPQVYDFLKQEQPVHGASIYYFRRVFHDWPDLPEGKKILDNTRAAMSREHSRILIHDIIVPEIGATMSHAWQDLSLMAIGGMERTEKDFARLLDIAGLALVKVWRKPGDMMGIIEARLK
UniProtKB AC: A0A1B2TT09 (positions: 8-405)
Coverage: 98%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Dimeric O-methyltransferase
Evidence level: Indirect evidence
Evidence coverage: Only some parts of the structure participates in mutual synergistic folding.
Complex Evidence:
Coniferyl alcohol 9-O-methyltransferase has an intertwined dimeric structure with large relative interaction surface. The active site is formed by both monomers and thus dimerization is critical for activity. The N-terminal helices form the dimerization subdomain and at the same time form the rear wall of the active-site cavity in the neighbouring monomer (PMID:23633600). Other 9-O-methyltransferase structures show similar features and exhibit no monomeric form in solution (PMID:11224575).
Chain A:
N/A
Chain A-2:
N/A
Surface and contacts features:
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). Download the CIF file (.cif)
Download this entry's XML file (.xml)
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