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- EMDB-46506: Cryo-EM structure of mycocerosic acid synthase with a single DH-A... -

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Basic information

Entry
Database: EMDB / ID: EMD-46506
TitleCryo-EM structure of mycocerosic acid synthase with a single DH-ACP crosslink using C16 alpha-bromoamide. Complex C
Map datamain map
Sample
  • Complex: Homodimeric MAS single crosslink between ACP and DH domains
    • Protein or peptide: Mycocerosic acid synthase
  • Ligand: N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alaninamide
KeywordsFAS / polyketide / crosslinked / dehydratase / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


mycocerosate synthase activity / mycocerosate synthase / DIM/DIP cell wall layer assembly / fatty acid synthase activity / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / fatty acid biosynthetic process / oxidoreductase activity / plasma membrane / cytoplasm
Similarity search - Function
: / Zinc-binding dehydrogenase / : / Polyketide synthase dehydratase N-terminal domain / Polyketide synthase, dehydratase domain / PKS_DH / : / Polyketide synthase dehydratase domain / : / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. ...: / Zinc-binding dehydrogenase / : / Polyketide synthase dehydratase N-terminal domain / Polyketide synthase, dehydratase domain / PKS_DH / : / Polyketide synthase dehydratase domain / : / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Polyketide synthase, ketoreductase domain / KR domain / Malonyl-CoA ACP transacylase, ACP-binding / : / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase domain superfamily / Alcohol dehydrogenase, N-terminal / Alcohol dehydrogenase GroES-like domain / Polyketide synthase, enoylreductase domain / Enoylreductase / Acyl transferase/acyl hydrolase/lysophospholipase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / PKS_KR / Beta-ketoacyl synthase / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Ketosynthase family 3 (KS3) domain profile. / Beta-ketoacyl synthase, N-terminal / Beta-ketoacyl synthase, C-terminal / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase, N-terminal domain / Beta-ketoacyl synthase, C-terminal domain / GroES-like superfamily / Thiolase-like / Phosphopantetheine attachment site / Phosphopantetheine attachment site. / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Prokaryotic membrane lipoprotein lipid attachment site profile. / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
Mycocerosic acid synthase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.74 Å
AuthorsHeberlig GW / Jiang Z / Burkart MD
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM095970 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)K12 HL141956 United States
National Science Foundation (NSF, United States)DMR-2011924 United States
CitationJournal: Nat Commun / Year: 2025
Title: Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase.
Authors: Ziran Jiang / Graham W Heberlig / Jeffrey A Chen / Jennifer Huynh / James J La Clair / Michael D Burkart /
Abstract: Using a combination of dual covalent crosslinking and cryo-EM analyses, we elucidate the structure of mycocerosic acid synthase from Mycobacterium tuberculosis trapped in two distinct catalytic ...Using a combination of dual covalent crosslinking and cryo-EM analyses, we elucidate the structure of mycocerosic acid synthase from Mycobacterium tuberculosis trapped in two distinct catalytic states during its iterative cycle. These structures reveal domain architecture of the acyl carrier protein mediating condensation and dehydration through dual site-selective crosslinking of the acyl carrier protein with the ketosynthase and dehydratase domains. Map density was sufficient to visualize full domain architecture with active site-bound probes and elucidate key interactions of four distinct crosslinked species. Here, iterative vectorial polyketide biosynthesis arises through an overall twisting and tilting architecture, enabling positioning and entry of the cognate substrate at each enzymatic domain. These structures present valuable details for future therapeutic design against mycocerosic acid biosynthesis in M. tuberculosis.
History
DepositionAug 9, 2024-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46506.png

Downloads & links

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Map

FileDownload / File: emd_46506.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.89 Å/pix.
x 384 pix.
= 341.376 Å		0.89 Å/pix.
x 384 pix.
= 341.376 Å		0.89 Å/pix.
x 384 pix.
= 341.376 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.889 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.065
Minimum - Maximum-0.26685175 - 0.551796
Average (Standard dev.)0.00028467574 (±0.014044237)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 341.376 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half A

Fileemd_46506_half_map_1.map
Annotationhalf A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half B

Fileemd_46506_half_map_2.map
Annotationhalf B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homodimeric MAS single crosslink between ACP and DH domains

EntireName: Homodimeric MAS single crosslink between ACP and DH domains
Components
  • Complex: Homodimeric MAS single crosslink between ACP and DH domains
    • Protein or peptide: Mycocerosic acid synthase
  • Ligand: N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alaninamide

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Supramolecule #1: Homodimeric MAS single crosslink between ACP and DH domains

SupramoleculeName: Homodimeric MAS single crosslink between ACP and DH domains
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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Macromolecule #1: Mycocerosic acid synthase

MacromoleculeName: Mycocerosic acid synthase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: mycocerosate synthase
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 226.132672 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MESRVTPVAV IGMGCRLPGG INSPDKLWES LLRGDDLVTE IPPDRWDADD YYDPEPGVPG RSVSRWGGFL DDVAGFDAEF FGISEREAT SIDPQQRLLL ETSWEAIEHA GLDPASLAGS STAVFTGLTH EDYLVLTTTA GGLASPYVVT GLNNSVASGR I AHTLGLHG ...String:
MESRVTPVAV IGMGCRLPGG INSPDKLWES LLRGDDLVTE IPPDRWDADD YYDPEPGVPG RSVSRWGGFL DDVAGFDAEF FGISEREAT SIDPQQRLLL ETSWEAIEHA GLDPASLAGS STAVFTGLTH EDYLVLTTTA GGLASPYVVT GLNNSVASGR I AHTLGLHG PAMTFDTACS SGLMAVHLAC RSLHDGEADL ALAGGCAVLL EPHASVAASA QGMLSSTGRC HSFDADADGF VR SEGCAMV LLKRLPDALR DGNRIFAVVR GTATNQDGRT ETLTMPSEDA QVAVYRAALA AAGVQPETVG VVEAHGTGTP IGD PIEYRS LARVYGAGTP CALGSAKSNM GHSTASAGTV GLIKAILSLR HGVVPPLLHF NRLPDELSDV ETGLFVPQAV TPWP NGNDH TPKRVAVSSF GMSGTNVHAI VEEAPAEASA PESSPGDAEV GPRLFMLSST SSDALRQTAR QLATWVEEHQ DCVAA SDLA YTLARGRAHR PVRTAVVAAN LPELVEGLRE VADGDALYDA AVGHGDRGPV WVFSGQGSQW AAMGTQLLAS EPVFAA TIA KLEPVIAAES GFSVTEAITA QQTVTGIDKV QPAVFAVQVA LAATMEQTYG VRPGAVVGHS MGESAAAVVA GALSLED AA RVICRRSKLM TRIAGAGAMG SVELPAKQVN SELMARGIDD VVVSVVASPQ STVIGGTSDT VRDLIARWEQ RDVMAREV A VDVASHSPQV DPILDDLAAA LADIAPMTPK VPYYSATLFD PREQPVCDGA YWVDNLRNTV QFAAAVQAAM EDGYRVFAE LSPHPLLTHA VEQTGRSLDM SVAALAGMRR EQPLPHGLRG LLTELHRAGA ALDYSALYPA GRLVDAPLPA WTHARLFIDD DGQEQRAQG ACTITVHPLL GSHVRLTEEP ERHVWQGDVG TSVLSWLSDH QVHNVAALPG AAYCEMALAA AAEVFGEAAE V RDITFEQM LLLDEQTPID AVASIDAPGV VNFTVETNRD GETTRHATAA LRAAEDDCPP PGYDITALLQ AHPHAVNGTA MR ESFAERG VTLGAAFGGL TTAHTAEAGA ATVLAEVALP ASIRFQQGAY RIHPALLDAC FQSVGAGVQA GTATGGLLLP LGV RSLRAY GPTRNARYCY TRLTKAFNDG TRGGEADLDV LDEHGTVLLA VRGLRMGTGT SERDERDRLV SERLLTLGWQ QRAL PEVGD GEAGSWLLID TSNAVDTPDM LASTLTDALK SHGPQGTECA SLSWSVQDTP PNDQAGLEKL GSQLRGRDGV VIVYG PRVG DPDEHSLLAG REQVRHLVRI TRELAEFEGE LPRLFVVTRQ AQIVKPHDSG ERANLEQAGL RGLLRVISSE HPMLRT TLI DVDEHTDVER VAQQLLSGSE EDETAWRNGD WYVARLTPSP LGHEERRTAV LDPDHDGMRV QVRRPGDLQT LEFVASD RV PPGPGQIEVA VSMSSINFAD VLIAFGRFPI IDDREPQLGM DFVGVVTAVG EGVTGHQVGD RVGGFSEGGC WRTFLTCD A NLAVTLPPGL TDEQAITAAT AHATAWYGLN DLAQIKAGDK VLIHSATGGV GQAAISIARA KGAEIFATAG NPAKRAMLR DMGVEHVYDS RSVEFAEQIR RDTDGYGVDI VLNSLTGAAQ RAGLELLAFG GRFVEIGKAD VYGNTRLGLF PFRRGLTFYY LDLALMSVT QPDRVRELLA TVFKLTADGV LTAPQCTHYP LAEAADAIRA MSNAEHTGKL VLDVPRSGRR SVAVTPEQAP L YRRDGSYI ITGGLGGLGL FFASKLAAAG CGRIVLTARS QPNPKARQTI EGLRAAGADI VVECGNIAEP DTADRLVSAA TA TGLPLRG VLHSAAVVED ATLTNITDEL IDRDWSPKVF GSWNLHRATL GQPLDWFCLF SSGAALLGSP GQGAYAAANS WVD VFAHWR RAQGLPVSAI AWGAWGEVGR ATFLAEGGEI MITPEEGAYA FETLVRHDRA YSGYIPILGA PWLADLVRRS PWGE MFAST GQRSRGPSKF RMELLSLPQD EWAGRLRRLL VEQASVILRR TIDADRSFIE YGLDSLGMLE MRTHVETETG IRLTP KVIA TNNTARALAQ YLADTLAEEQ AAAPAASKLA AALEHHHHHH

UniProtKB: Mycocerosic acid synthase

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Macromolecule #2: N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-...

MacromoleculeName: N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alaninamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: MU4
Molecular weightTheoretical: 579.707 Da
Chemical component information

ChemComp-MU4:
N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alaninamide

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
50.0 mMTris HCl
150.0 mMSodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 3135 / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1055614
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.74 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 35969
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1-f1


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-9d30:
Cryo-EM structure of mycocerosic acid synthase with a single DH-ACP crosslink using C16 alpha-bromoamide. Complex C

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