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- PDB-7cpy: Lovastatin nonaketide synthase with LovC -

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Basic information

Entry
Database: PDB / ID: 7cpy
TitleLovastatin nonaketide synthase with LovC
Components
  • Lovastatin nonaketide synthase, enoyl reductase component lovC
  • Lovastatin nonaketide synthase, polyketide synthase component
KeywordsBIOSYNTHETIC PROTEIN / polyketide synthase
Function / homology
Function and homology information


malonyl-CoA metabolic process / lovastatin nonaketide synthase / lovastatin nonaketide synthase activity / polyketide synthase activity / lovastatin biosynthetic process / polyketide biosynthetic process / NADPH oxidation / S-adenosylmethionine metabolic process / oxidoreductase activity, acting on NAD(P)H / enoyl-[acyl-carrier-protein] reductase (NADH) activity ...malonyl-CoA metabolic process / lovastatin nonaketide synthase / lovastatin nonaketide synthase activity / polyketide synthase activity / lovastatin biosynthetic process / polyketide biosynthetic process / NADPH oxidation / S-adenosylmethionine metabolic process / oxidoreductase activity, acting on NAD(P)H / enoyl-[acyl-carrier-protein] reductase (NADH) activity / S-adenosylmethionine-dependent methyltransferase activity / acyltransferase activity, transferring groups other than amino-acyl groups / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / NADPH binding / fatty acid biosynthetic process / methylation / oxidoreductase activity / ATP binding
Similarity search - Function
: / Methyltransferase type 12 / Methyltransferase domain / Polyketide synthase dehydratase N-terminal domain / Condensation domain / Condensation domain / PKS_DH / Polyketide synthase, dehydratase domain / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, ketoreductase domain ...: / Methyltransferase type 12 / Methyltransferase domain / Polyketide synthase dehydratase N-terminal domain / Condensation domain / Condensation domain / PKS_DH / Polyketide synthase, dehydratase domain / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, ketoreductase domain / KR domain / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Malonyl-CoA ACP transacylase, ACP-binding / Acyl transferase domain superfamily / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase/acyl hydrolase/lysophospholipase / Chloramphenicol acetyltransferase-like domain superfamily / Alcohol dehydrogenase, N-terminal / Alcohol dehydrogenase GroES-like domain / Polyketide synthase, enoylreductase domain / Enoylreductase / Ketosynthase family 3 (KS3) domain profile. / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / Beta-ketoacyl synthase / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase, N-terminal / Beta-ketoacyl synthase, C-terminal / Beta-ketoacyl synthase, N-terminal domain / Beta-ketoacyl synthase, C-terminal domain / GroES-like superfamily / Thiolase-like / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / NAD(P)-binding domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Lovastatin nonaketide synthase, enoyl reductase component lovC / Lovastatin nonaketide synthase, polyketide synthase component
Similarity search - Component
Biological speciesAspergillus terreus (mold)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsWang, J. / Wang, Z.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31470830 China
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis for the biosynthesis of lovastatin.
Authors: Jialiang Wang / Jingdan Liang / Lu Chen / Wei Zhang / Liangliang Kong / Chao Peng / Chen Su / Yi Tang / Zixin Deng / Zhijun Wang /
Abstract: Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), ...Statins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB-LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB-LovC complex at 3.60 Å and the core LovB at 2.91 Å resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.
History
DepositionAug 8, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2021Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.2Dec 15, 2021Group: Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / database_2
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
C: Lovastatin nonaketide synthase, enoyl reductase component lovC
D: Lovastatin nonaketide synthase, enoyl reductase component lovC
A: Lovastatin nonaketide synthase, polyketide synthase component
B: Lovastatin nonaketide synthase, polyketide synthase component
hetero molecules


Theoretical massNumber of molelcules
Total (without water)755,6266
Polymers754,1394
Non-polymers1,4872
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Lovastatin nonaketide synthase, enoyl reductase component lovC / / Lovastatin biosynthesis cluster protein C / Trans-enoyl reductase lovC


Mass: 40622.891 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aspergillus terreus (mold) / Gene: lovC / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y7D0, lovastatin nonaketide synthase
#2: Protein Lovastatin nonaketide synthase, polyketide synthase component / / LNKS / Lovastatin biosynthesis cluster protein B


Mass: 336446.656 Da / Num. of mol.: 2 / Mutation: G1884Q, Q1885A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aspergillus terreus (mold) / Gene: lovB / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q9Y8A5, lovastatin nonaketide synthase
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1LovBC complexCOMPLEX#1-#20RECOMBINANT
2lovCCOMPLEX#11RECOMBINANT
3lovBCOMPLEX#21RECOMBINANT
Molecular weightValue: 750 kDa/nm / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Aspergillus terreus (mold)33178
32Aspergillus terreus (mold)33178
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Saccharomyces cerevisiae (brewer's yeast)4932
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was homogeneous
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60.8 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: SerialEM / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 83573 / Symmetry type: POINT

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