PDBsum entry: 1w93

Ligase

PDB-id: 1w93

Contents

Description

Header details

Header records

References

PROCHECK

Protein chain

549 a.a. *

Waters ×149

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

1w93

Name:

Ligase

Title:

Crystal structure of biotin carboxylase domain of acetyl- coenzyme a carboxylase from saccharomyces cerevisiae

Structure:

Acetyl-coenzyme a carboxylase. Chain: a. Fragment: biotin carboxylase domain, residues 14-566. Synonym: acc. Engineered: yes

Source:

Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562

UniProt:

Q00955 (ACAC_YEAST)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

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Struc:

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Struc:

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Struc:

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Struc:

Seq:

Struc:

Seq:

2233 a.a.

Struc:

549 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

Enzyme class 1:

E.C.6.3.4.14   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + biotin-carboxyl-carrier protein + CO₂ = ADP + phosphate + carboxybiotin-carboxyl-carrier protein (see diagram below)

Enzyme class 2:

E.C.6.4.1.2   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + acetyl-CoA + HCO₃^- = ADP + phosphate + malonyl-CoA (see diagram below)

Cofactor:

Biotin

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Resolution:

2.50Å

R-factor:

0.254

R-free:

0.323

Authors:

Y.Shen,S.L.Volrath,S.C.Weatherly,T.D.Elich,L.Tong

Key ref:

Y.Shen et al. (2004). A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product.. Mol Cell, 16, 881-891. [PubMed id: 15610732] [DOI: 10.1016/j.molcel.2004.11.034]

Date:

05-Oct-04

Release date:

04-Jan-05

Related entries:

1od2 acetyl-coa carboxylase carboxyltransferas domaine
1od4 acetyl-coa carboxylase carboxyltransferase domain
1uyr acetyl-coa carboxylase carboxyltransferase domain in complex with inhibitor diclofop
1uys acetyl-coa carboxylase carboxyltransferase domain in complex with inhibitor haloxyfop
1uyt acetyl-coa carboxylase carboxyltransferase domain
1uyv acetyl-coa carboxylase carboxyltransferase domain l1705i/v1967i mutant
1w2x crystal structure of the carboxyltransferase domain of acetyl-coenzyme a carboxylase in complex with cp-640186

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Clefts

Surface

Key reference

DOI no: 10.1016/j.molcel.2004.11.034

Mol Cell 16:881-891 (2004)

PubMed id: 15610732

A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product.

Y.Shen, S.L.Volrath, S.C.Weatherly, T.D.Elich, L.Tong.

ABSTRACT

Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism. Soraphen A, a macrocyclic polyketide natural product, is a nanomolar inhibitor against the biotin carboxylase (BC) domain of human, yeast, and other eukaryotic ACCs. Here we report the crystal structures of the yeast BC domain, alone and in complex with soraphen A. Soraphen has extensive interactions with an allosteric site, about 25 A from the active site. The specificity of soraphen is explained by large structural differences between the eukaryotic and prokaryotic BC in its binding site, confirmed by our studies on the effects of single-site mutations in this binding site. Unexpectedly, our structures suggest that soraphen may bind in the BC dimer interface and inhibit the BC activity by disrupting the oligomerization of this domain. Observations from native gel electrophoresis confirm this structural insight. The structural information provides a foundation for structure-based design of new inhibitors against these enzymes.

Selected figure(s)

Figure 2.
Figure 2. Structure of Biotin Carboxylase in Complex with Soraphen A(A) Chemical structure of soraphen A. The numbering scheme of atoms in the macrocycle is shown.(B) Final 2F[o] − F[c] electron density at 1.8 Å resolution for soraphen A, contoured at 1σ. Produced with Setor (Evans, 1993).(C) Schematic drawing of the structure of yeast BC domain in complex with soraphen A. Residues 535–538 (in the αR-αS loop) are disordered in this molecule and are shown in gray. Soraphen A is shown as a stick model in green for carbon atoms, labeled Sor. The expected position of ATP, as observed in the E. coli BC subunit (Thoden et al., 2000), is shown in gray.(D) Side view of the structure of the BC:soraphen complex. The different domains are colored differently. (C) and (D) were produced with Ribbons (Carson, 1987).

Figure 3.
Figure 3. The Binding Mode of Soraphen A(A) Stereographic drawing showing the binding site for soraphen A. Produced with Ribbons (Carson, 1987).(B) Schematic drawing of the interactions between soraphen A and the BC domain.(C) Molecular surface of the BC domain in the soraphen binding site. Produced with Grasp (Nicholls et al., 1991).

The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 16, 881-891) copyright 2004.

Figures were selected by an automated process.