6J24

Crystal structure of a SAM-dependent methyltransferase LepI in complex with its substrate

Summary for 6J24

• Entry DOI: 10.2210/pdb6j24/pdb
• Descriptor: O-methyltransferase, (3~{S},4'~{R},4'~{a}~{S},6'~{R},8'~{a}~{S})-4',6'-dimethyl-5-phenyl-spiro[1~{H}-pyridine-3,5'-2,3,4,4~{a},6,8~{a}-hexahydro-1~{H}-naphthalene]-2,4-dione, S-ADENOSYLMETHIONINE, ... (4 entities in total)
• Functional Keywords: complex, transferase
• Biological source: Aspergillus flavus
• Total number of polymer chains: 2
• Total formula weight: 88196.74

Authors

Qiu, S.,Wei, C. (deposition date: 2018-12-30, release date: 2019-05-01, Last modification date: 2023-11-22)

Primary citation

Sun, Q.,Hu, Y.,Gu, Y.,Huang, J.,He, J.,Luo, L.,Yang, Y.,Yin, S.,Dou, C.,Wang, T.,Fu, X.,He, L.,Qi, S.,Zhu, X.,Yang, S.,Wei, X.,Cheng, W.
Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme.
Signal Transduct Target Ther, 4:17-17, 2019

PubMed Abstract: -adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5'-deoxy-5'-(methylthio) adenosine (MTA), -adenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.

PubMed: 31149354
DOI: 10.1038/s41392-019-0052-y

Experimental method

X-RAY DIFFRACTION (2.244 Å)