8j7d

From Proteopedia

Human 3-methylcrotonyl-CoA carboxylase in BCCP-H1 state

Structural highlights

8j7d is a 12 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 2.7Å
Ligands:	BTI
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MCCA_HUMAN Defects in MCCC1 are the cause of methylcrotonoyl-CoA carboxylase 1 deficiency (MCC1D) [MIM:210200. An autosomal recessive disorder of leucine catabolism. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency.^[1] ^[2] ^[3] ^[4]

Function

MCCA_HUMAN

Publication Abstract from PubMed

The enzymes 3-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), pyruvate carboxylase and propionyl-CoA carboxylase belong to the biotin-dependent carboxylase family located in mitochondria. They participate in various metabolic pathways in human such as amino acid metabolism and tricarboxylic acid cycle. Many human diseases are caused by mutations in those enzymes but their structures have not been fully resolved so far. Here we report an optimized purification strategy to obtain high-resolution structures of intact human endogenous MCC, propionyl-CoA carboxylase and pyruvate carboxylase in different conformational states. We also determine the structures of MCC bound to different substrates. Analysis of MCC structures in different states reveals the mechanism of the substrate-induced, multi-element synergistic activation of MCC. These results provide important insights into the catalytic mechanism of the biotin-dependent carboxylase family and are of great value for the development of new drugs for the treatment of related diseases.

Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase.,Su J, Tian X, Cheng H, Liu D, Wang Z, Sun S, Wang HW, Sui SF Nat Struct Mol Biol. 2024 Sep 2. doi: 10.1038/s41594-024-01379-3. PMID:39223421^[5]

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

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Citations

reviews cite this structure

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References

↑ Gallardo ME, Desviat LR, Rodriguez JM, Esparza-Gordillo J, Perez-Cerda C, Perez B, Rodriguez-Pombo P, Criado O, Sanz R, Morton DH, Gibson KM, Le TP, Ribes A, de Cordoba SR, Ugarte M, Penalva MA. The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. Am J Hum Genet. 2001 Feb;68(2):334-46. Epub 2001 Jan 17. PMID:11170888 doi:S0002-9297(07)64086-5
↑ Holzinger A, Roschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA. Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency. Hum Mol Genet. 2001 Jun 1;10(12):1299-306. PMID:11406611
↑ Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D. The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest. 2001 Feb;107(4):495-504. PMID:11181649 doi:10.1172/JCI11948
↑ Cho SY, Park HD, Lee YW, Ki CS, Lee SY, Sohn YB, Park SW, Kim SH, Ji S, Kim SJ, Choi EW, Kim CH, Ko AR, Paik KH, Lee DH, Jin DK. Mutational spectrum in eight Korean patients with 3-methylcrotonyl-CoA carboxylase deficiency. Clin Genet. 2012 Jan;81(1):96-8. doi: 10.1111/j.1399-0004.2011.01704.x. PMID:22150417 doi:10.1111/j.1399-0004.2011.01704.x
↑ Su J, Tian X, Cheng H, Liu D, Wang Z, Sun S, Wang HW, Sui SF. Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase. Nat Struct Mol Biol. 2024 Sep 2. PMID:39223421 doi:10.1038/s41594-024-01379-3