6AL8

Crystal structure HpiC1 Y101F/F138S

Summary for 6AL8

• Entry DOI: 10.2210/pdb6al8/pdb
• Related: 5WPP 5WPR 5WPS 5WPU 6AL6 6AL7
• Descriptor: 12-epi-hapalindole C/U synthase, CALCIUM ION, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: isomerase, cyclase
• Biological source: Fischerella sp. ATCC 43239
• Total number of polymer chains: 4
• Total formula weight: 98419.13

Authors

Newmister, S.A.,Li, S.,Garcia-Borras, M.,Sanders, J.N.,Yang, S.,Lowell, A.N.,Yu, F.,Smith, J.L.,Williams, R.M.,Houk, K.N.,Sherman, D.H. (deposition date: 2017-08-07, release date: 2018-03-07, Last modification date: 2024-03-13)

Primary citation

Newmister, S.A.,Li, S.,Garcia-Borras, M.,Sanders, J.N.,Yang, S.,Lowell, A.N.,Yu, F.,Smith, J.L.,Williams, R.M.,Houk, K.N.,Sherman, D.H.
Structural basis of the Cope rearrangement and cyclization in hapalindole biogenesis.
Nat. Chem. Biol., 14:345-351, 2018

PubMed Abstract: Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5-Å structure revealed a dimeric assembly with two calcium ions per monomer and with the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid-catalyzed [3,3]-sigmatropic rearrangement, as well as specific determinants that control the position of terminal electrophilic aromatic substitution, leading to a switch from hapalindole to fischerindole alkaloids.

PubMed: 29531360
DOI: 10.1038/s41589-018-0003-x

Experimental method

X-RAY DIFFRACTION (1.641 Å)