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- PDB-6vvq: Human START domain of Acyl-coenzyme A thioesterase 11 (ACOT11) bo... -

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Basic information

Entry
Database: PDB / ID: 6vvq
TitleHuman START domain of Acyl-coenzyme A thioesterase 11 (ACOT11) bound to Myristic Acid
ComponentsAcyl-coenzyme A thioesterase 11
KeywordsLIPID BINDING PROTEIN / START / Lipid / Thioesterase / Allostery
Function / homology
Function and homology information


long-chain fatty acyl-CoA hydrolase activity / palmitoyl-CoA hydrolase / acyl-CoA metabolic process / fatty acyl-CoA hydrolase activity / Mitochondrial Fatty Acid Beta-Oxidation / Hydrolases; Acting on ester bonds; Thioester hydrolases / carboxylic ester hydrolase activity / negative regulation of cold-induced thermogenesis / response to temperature stimulus / response to cold ...long-chain fatty acyl-CoA hydrolase activity / palmitoyl-CoA hydrolase / acyl-CoA metabolic process / fatty acyl-CoA hydrolase activity / Mitochondrial Fatty Acid Beta-Oxidation / Hydrolases; Acting on ester bonds; Thioester hydrolases / carboxylic ester hydrolase activity / negative regulation of cold-induced thermogenesis / response to temperature stimulus / response to cold / fatty acid metabolic process / intracellular signal transduction / mitochondrial matrix / lipid binding / extracellular exosome / cytosol / cytoplasm
Similarity search - Function
Hotdog acyl-CoA thioesterase (ACOT)-type domain / Cytosolic acyl coenzyme A thioester hydrolase / Hotdog acyl-CoA thioesterase (ACOT)-type domain profile. / in StAR and phosphatidylcholine transfer protein / START domain / START domain / START domain profile. / Thioesterase domain / Thioesterase superfamily / HotDog domain superfamily / START-like domain superfamily
Similarity search - Domain/homology
MYRISTIC ACID / Acyl-coenzyme A thioesterase 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.09 Å
AuthorsTillman, M.C. / Ortlund, E.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK103046-06 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM008602 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine.
Authors: Matthew C Tillman / Norihiro Imai / Yue Li / Manoj Khadka / C Denise Okafor / Puneet Juneja / Akshitha Adhiyaman / Susan J Hagen / David E Cohen / Eric A Ortlund /
Abstract: Nonshivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold ambient temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally up-regulated in ...Nonshivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold ambient temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally up-regulated in brown adipose tissue upon exposure to the cold and suppresses thermogenesis in order to conserve energy reserves. It hydrolyzes long-chain fatty acyl-CoAs that are derived from lipid droplets, preventing their use as fuel for thermogenesis. In addition to its enzymatic domains, Them1 contains a C-terminal StAR-related lipid transfer (START) domain with unknown ligand or function. By complementary biophysical approaches, we show that the START domain binds to long-chain fatty acids, products of Them1's enzymatic reaction, as well as lysophosphatidylcholine (LPC), lipids shown to activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the START domain and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the START domain functions to localize Them1 near lipid droplets. These findings define the role of the START domain as a lipid sensor that allosterically regulates Them1 activity and spatially localizes it in proximity to the lipid droplet.
History
DepositionFeb 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Acyl-coenzyme A thioesterase 11
B: Acyl-coenzyme A thioesterase 11
C: Acyl-coenzyme A thioesterase 11
D: Acyl-coenzyme A thioesterase 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,9025
Polymers118,6744
Non-polymers2281
Water1629
1
A: Acyl-coenzyme A thioesterase 11


Theoretical massNumber of molelcules
Total (without water)29,6681
Polymers29,6681
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Acyl-coenzyme A thioesterase 11


Theoretical massNumber of molelcules
Total (without water)29,6681
Polymers29,6681
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Acyl-coenzyme A thioesterase 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8972
Polymers29,6681
Non-polymers2281
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Acyl-coenzyme A thioesterase 11


Theoretical massNumber of molelcules
Total (without water)29,6681
Polymers29,6681
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.082, 70.984, 127.224
Angle α, β, γ (deg.)90.000, 96.133, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein
Acyl-coenzyme A thioesterase 11 / Acyl-CoA thioesterase 11 / Acyl-CoA thioester hydrolase 11 / Adipose-associated thioesterase / ...Acyl-CoA thioesterase 11 / Acyl-CoA thioester hydrolase 11 / Adipose-associated thioesterase / Brown fat-inducible thioesterase / BFIT / Palmitoyl-coenzyme A thioesterase


Mass: 29668.473 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACOT11, BFIT, KIAA0707, THEA / Variant: Isoform 2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q8WXI4, Hydrolases; Acting on ester bonds; Thioester hydrolases, palmitoyl-CoA hydrolase
#2: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.46 Å3/Da / Density % sol: 50.04 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 9.4 / Details: 0.1 M Tris HCl pH 9.4 and 27 % PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 21217 / % possible obs: 99.3 % / Redundancy: 5.8 % / Biso Wilson estimate: 73.76 Å2 / Rpim(I) all: 0.121 / Rrim(I) all: 0.304 / Net I/σ(I): 11.3
Reflection shellResolution: 3.1→3.21 Å / Num. unique obs: 2083 / CC1/2: 0.647 / Rpim(I) all: 0.71 / % possible all: 99.7

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Processing

Software
NameVersionClassification
HKL-20001.14_3260data scaling
PHENIX1.14_3260refinement
PHENIX1.14_3260phasing
HKL-2000data collection
HKL-2000data scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3fo5

3fo5


Resolution: 3.09→42.99 Å / SU ML: 0.3992 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.3471 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2632 1061 5.01 %
Rwork0.2209 20132 -
obs0.2231 21193 98.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 80.72 Å2
Refinement stepCycle: LAST / Resolution: 3.09→42.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7489 0 16 9 7514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027674
X-RAY DIFFRACTIONf_angle_d0.459610413
X-RAY DIFFRACTIONf_chiral_restr0.03951150
X-RAY DIFFRACTIONf_plane_restr0.0031338
X-RAY DIFFRACTIONf_dihedral_angle_d2.65264630
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.09-3.230.33921260.30312386X-RAY DIFFRACTION94.83
3.23-3.40.37171310.2742497X-RAY DIFFRACTION99.1
3.4-3.610.2731320.23472510X-RAY DIFFRACTION99.32
3.61-3.890.32861330.23532509X-RAY DIFFRACTION99.44
3.89-4.280.29161330.21152530X-RAY DIFFRACTION99.25
4.28-4.90.21741330.17132534X-RAY DIFFRACTION99.55
4.9-6.170.21251350.21652559X-RAY DIFFRACTION99.67
6.17-42.990.24131380.22152607X-RAY DIFFRACTION99.06

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