10QU
Crystal structure of an O-methyltransferase (Dol15G) from dolastatin 15 biosynthesis in complex with S-adenosyl-L-homocysteine (SAH)
Summary for 10QU
| Entry DOI | 10.2210/pdb10qu/pdb |
| Descriptor | O-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | o-methyltransferase, transferase |
| Biological source | Cyanobacteriota |
| Total number of polymer chains | 2 |
| Total formula weight | 75674.09 |
| Authors | |
| Primary citation | Chen, M.,Liu, J.,Tsai, H.Y.,Li, C.Y.,Batucan, J.D.,Eckhardt, C.W.,Pham, T.H.D.,Ellis, E.K.,Ratnayake, R.,Paul, V.J.,Bruner, S.D.,Donia, M.S.,Luesch, H.,Ding, Y. Biosynthetic origin of anticancer dolastatin 15 reveals a noncanonical NRPS architecture enabling 2-keto acid activation. Proc.Natl.Acad.Sci.USA, 123:e2615454123-e2615454123, 2026 Cited by PubMed Abstract: Elucidating the biological origins and biosynthetic pathways of marine natural products remains a major challenge, particularly for compounds derived from microbial consortia. Here, we identify the marine cyanobacterial genus as the source of the potent anticancer natural product dolastatin 15 using genome-resolved metagenomics. Reconstruction of two complete and two near-complete genomes provides genome-resolved characterization of the genus , revealing extensive biosynthetic potential. Genome mining identified the dolastatin 15 biosynthetic gene cluster. Subsequent analyses reconstructed its pathway and uncovered a noncanonical five-domain nonribosomal peptide synthetase module containing an embedded 2-keto acid-activating domain, revealing an unexpected architectural solution for incorporating 2-keto acid-derived hydroxy acid building blocks. Comparative and evolutionary analyses support a model in which this architecture may have arisen through recruitment of keto acid-activating domains and reduction of canonical adenylation domain features. We further biochemically and structurally characterize an -methyltransferase that catalyzes formation of the characteristic methoxy pyrrolinone moiety, thereby validating a key terminal tailoring step in the proposed biosynthetic pathway. Together, these findings define the biosynthetic logic of dolastatin 15 and expand understanding of substrate activation and assembly-line diversification in nonribosomal peptide biosynthesis. PubMed: 42809394DOI: 10.1073/pnas.2615454123 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
Download full validation report
