9uh8: Difference between revisions

Latest revision as of 07:52, 19 November 2025

BCCP-BC Conformation of AMPPNP-bound hPCC

Structural highlights

9uh8 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.98Å
Ligands:	1VU, ANP, BCT, BTN, MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PCCA_HUMAN Defects in PCCA are the cause of propionic acidemia type I (PA-1) [MIM:606054. PA-1 is a life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein.^[1] ^[2] ^[3] ^[4]

Function

PCCA_HUMAN

Publication Abstract from PubMed

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.

Nanoscale conformational dynamics of human propionyl-CoA carboxylase.,Yan H, Ni F, Wang Q, Ma J Structure. 2025 Nov 5:S0969-2126(25)00396-X. doi: 10.1016/j.str.2025.10.009. PMID:41197621^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Richard E, Desviat LR, Perez B, Perez-Cerda C, Ugarte M. Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. Biochim Biophys Acta. 1999 Mar 30;1453(3):351-8. PMID:10101253
↑ Perez B, Desviat LR, Rodriguez-Pombo P, Clavero S, Navarrete R, Perez-Cerda C, Ugarte M. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab. 2003 Jan;78(1):59-67. PMID:12559849
↑ Yang X, Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Yamaguchi S, Takahashi Y, Nishikubo T, Kawaguchi C, Yoshioka A, Kimura T, Hayasaka K, Kohno Y, Iinuma K, Ohura T. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Mol Genet Metab. 2004 Apr;81(4):335-42. PMID:15059621 doi:10.1016/j.ymgme.2004.01.003
↑ Campeau E, Dupuis L, Leon-Del-Rio A, Gravel R. Coding sequence mutations in the alpha subunit of propionyl-CoA carboxylase in patients with propionic acidemia. Mol Genet Metab. 1999 May;67(1):11-22. PMID:10329019 doi:10.1006/mgme.1999.2850
↑ Yan H, Ni F, Wang Q, Ma J. Nanoscale conformational dynamics of human propionyl-CoA carboxylase. Structure. 2025 Nov 5:S0969-2126(25)00396-X. PMID:41197621 doi:10.1016/j.str.2025.10.009

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Richard E, Desviat LR, Perez B, Perez-Cerda C, Ugarte M. Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein. Biochim Biophys Acta. 1999 Mar 30;1453(3):351-8. PMID:10101253

[2] Perez B, Desviat LR, Rodriguez-Pombo P, Clavero S, Navarrete R, Perez-Cerda C, Ugarte M. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab. 2003 Jan;78(1):59-67. PMID:12559849

[3] Yang X, Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Yamaguchi S, Takahashi Y, Nishikubo T, Kawaguchi C, Yoshioka A, Kimura T, Hayasaka K, Kohno Y, Iinuma K, Ohura T. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic acidemia. Mol Genet Metab. 2004 Apr;81(4):335-42. PMID:15059621 doi:10.1016/j.ymgme.2004.01.003

[4] Campeau E, Dupuis L, Leon-Del-Rio A, Gravel R. Coding sequence mutations in the alpha subunit of propionyl-CoA carboxylase in patients with propionic acidemia. Mol Genet Metab. 1999 May;67(1):11-22. PMID:10329019 doi:10.1006/mgme.1999.2850

[5] Yan H, Ni F, Wang Q, Ma J. Nanoscale conformational dynamics of human propionyl-CoA carboxylase. Structure. 2025 Nov 5:S0969-2126(25)00396-X. PMID:41197621 doi:10.1016/j.str.2025.10.009

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9uh8 is ON HOLD
+==BCCP-BC Conformation of AMPPNP-bound hPCC==
+<StructureSection load='9uh8' size='340' side='right'caption='[[9uh8]], [[Resolution|resolution]] 2.98&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9uh8]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9UH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9UH8 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.98&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1VU:PROPIONYL+COENZYME+A'>1VU</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=BTN:BIOTIN'>BTN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9uh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9uh8 OCA], [https://pdbe.org/9uh8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9uh8 RCSB], [https://www.ebi.ac.uk/pdbsum/9uh8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9uh8 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/PCCA_HUMAN PCCA_HUMAN] Defects in PCCA are the cause of propionic acidemia type I (PA-1) [MIM:[https://omim.org/entry/606054 606054]. PA-1 is a life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein.<ref>PMID:10101253</ref> <ref>PMID:12559849</ref> <ref>PMID:15059621</ref> <ref>PMID:10329019</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/PCCA_HUMAN PCCA_HUMAN]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-Authors:
+Nanoscale conformational dynamics of human propionyl-CoA carboxylase.,Yan H, Ni F, Wang Q, Ma J Structure. 2025 Nov 5:S0969-2126(25)00396-X. doi: 10.1016/j.str.2025.10.009. PMID:41197621<ref>PMID:41197621</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9uh8" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Ma JP]]
+[[Category: Ni FY]]
+[[Category: Wang QH]]
+[[Category: Yan HF]]

9uh8: Difference between revisions

Latest revision as of 07:52, 19 November 2025

BCCP-BC Conformation of AMPPNP-bound hPCC

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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