8ZUX

Structure of G668R-hPCC

Summary for 8ZUX

• Entry DOI: 10.2210/pdb8zux/pdb
• EMDB information: 60500
• Descriptor: Propionyl-CoA carboxylase alpha chain, mitochondrial, Propionyl-CoA carboxylase beta chain, mitochondrial, ADENOSINE-5'-TRIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: biotin, carboxylase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 139880.69

Authors

Ni, F.,Yan, H.,Wang, Q.,Ma, J. (deposition date: 2024-06-10, release date: 2025-11-19)

Primary citation

Yan, H.,Ni, F.,Wang, Q.,Ma, J.
Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
Structure, 2025

PubMed Abstract: Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC's catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.

PubMed: 41197621
DOI: 10.1016/j.str.2025.10.009

Experimental method

ELECTRON MICROSCOPY (2.68 Å)