Human CTP synthase filament structure reveals the active enzyme conformation. Author Eric Lynch, Derrick Hicks, Matthew Shepherd, James Endrizzi, Allison Maker, Jesse Hansen, Rachael Barry, Zemer Gitai, Enoch Baldwin, Justin Kollman Publication Year 2017 Type Journal Article Abstract The universally conserved enzyme CTP synthase (CTPS) forms filaments in bacteria and eukaryotes. In bacteria, polymerization inhibits CTPS activity and is required for nucleotide homeostasis. Here we show that for human CTPS, polymerization increases catalytic activity. The cryo-EM structures of bacterial and human CTPS filaments differ considerably in overall architecture and in the conformation of the CTPS protomer, explaining the divergent consequences of polymerization on activity. The structure of human CTPS filament, the first structure of the full-length human enzyme, reveals a novel active conformation. The filament structures elucidate allosteric mechanisms of assembly and regulation that rely on a conserved conformational equilibrium. The findings may provide a mechanism for increasing human CTPS activity in response to metabolic state and challenge the assumption that metabolic filaments are generally storage forms of inactive enzymes. Allosteric regulation of CTPS polymerization by ligands likely represents a fundamental mechanism underlying assembly of other metabolic filaments. Keywords Humans, Models, Molecular, Crystallography, X-Ray, Protein Conformation, Macromolecular Substances, Protein Multimerization, Cryoelectron Microscopy, Carbon-Nitrogen Ligases Journal Nat Struct Mol Biol Volume 24 Issue 6 Pages 507-514 Date Published 2017 Jun ISSN Number 1545-9985 DOI 10.1038/nsmb.3407 Alternate Journal Nat Struct Mol Biol PMCID PMC5472220 PMID 28459447 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML