+
Open data
-
Basic information
Entry | Database: EMDB / ID: EMD-24209 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Structure of nevanimibe bound human ACAT2 | |||||||||
![]() | Structure of nevanimibe bound human ACAT2 | |||||||||
![]() |
| |||||||||
![]() | Inhibitor / TRANSFERASE-Inhibitor complex | |||||||||
Function / homology | ![]() sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / cholesterol storage / very-low-density lipoprotein particle assembly / low-density lipoprotein particle clearance / fatty-acyl-CoA binding / intestinal cholesterol absorption / LDL clearance / cholesterol efflux ...sterol O-acyltransferase / sterol O-acyltransferase activity / cholesterol O-acyltransferase activity / cholesterol storage / very-low-density lipoprotein particle assembly / low-density lipoprotein particle clearance / fatty-acyl-CoA binding / intestinal cholesterol absorption / LDL clearance / cholesterol efflux / macrophage derived foam cell differentiation / acyltransferase activity / cholesterol binding / brush border / cholesterol metabolic process / cholesterol homeostasis / endoplasmic reticulum membrane / endoplasmic reticulum Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.93 Å | |||||||||
![]() | Li X / Long T | |||||||||
![]() | ![]() Title: Molecular structures of human ACAT2 disclose mechanism for selective inhibition. Authors: Tao Long / Yang Liu / Xiaochun Li / ![]() Abstract: Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored ...Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease. | |||||||||
History |
|
-
Structure visualization
Movie |
![]() |
---|---|
Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
-
Downloads & links
-EMDB archive
Map data | ![]() | 23.6 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 9.2 KB 9.2 KB | Display Display | ![]() |
Images | ![]() | 36.2 KB | ||
Filedesc metadata | ![]() | 5.1 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 361.1 KB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 360.7 KB | Display | |
Data in XML | ![]() | 7 KB | Display | |
Data in CIF | ![]() | 8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7n6rMC ![]() 7n6qC M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Structure of nevanimibe bound human ACAT2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.833 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-
Sample components
-Entire : human ACAT2 with nevanimibe
Entire | Name: human ACAT2 with nevanimibe |
---|---|
Components |
|
-Supramolecule #1: human ACAT2 with nevanimibe
Supramolecule | Name: human ACAT2 with nevanimibe / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1 |
---|---|
Source (natural) | Organism: ![]() |
-Macromolecule #1: Sterol O-acyltransferase 2
Macromolecule | Name: Sterol O-acyltransferase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: sterol O-acyltransferase |
---|---|
Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 60.893 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MDYKDDDDKE PGGARLRLQR TGGLGGERER QPCGDGNTET HRAPDLVQWT RHMEAVKAQL LEQAQGQLRE LLDRAMREAI QSYPSQDKP LPPPPPGSLS RTQEPSLGKQ KVFIIRKSLL DELMEVQHFR TIYHMFIAGL CVFIISTLAI DFIDEGRLLL E FDLLIFSF ...String: MDYKDDDDKE PGGARLRLQR TGGLGGERER QPCGDGNTET HRAPDLVQWT RHMEAVKAQL LEQAQGQLRE LLDRAMREAI QSYPSQDKP LPPPPPGSLS RTQEPSLGKQ KVFIIRKSLL DELMEVQHFR TIYHMFIAGL CVFIISTLAI DFIDEGRLLL E FDLLIFSF GQLPLALVTW VPMFLSTLLA PYQALRLWAR GTWTQATGLG CALLAAHAVV LCALPVHVAV EHQLPPASRC VL VFEQVRF LMKSYSFLRE AVPGILRARR GEGIQAPSFS SYLYFLFCPT LIYRETYPRT PYVRWNYVAK NFAQALGCVL YAC FILGRL CVPVFANMSR EPFSTRALVL SILHATLPGI FMLLLIFFAF LHCWLNAFAE MLRFGDRMFY RDWWNSTSFS NYYR TWNVV VHDWLYSYVY QDGLRLLGAR ARGVAMLGVF LVSAVAHEYI FCFVLGFFYP VMLILFLVIG GMLNFMMHDQ RTGPA WNVL MWTMLFLGQG IQVSLYCQEW YARRHCPLPQ ATFWGLVTPR SWSCHT UniProtKB: Sterol O-acyltransferase 2 |
-Macromolecule #2: nevanimibe
Macromolecule | Name: nevanimibe / type: ligand / ID: 2 / Number of copies: 4 / Formula: ROV |
---|---|
Molecular weight | Theoretical: 421.618 Da |
Chemical component information | ![]() ChemComp-ROV: |
-Macromolecule #3: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 8 / Formula: CLR |
---|---|
Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Macromolecule #4: OLEIC ACID
Macromolecule | Name: OLEIC ACID / type: ligand / ID: 4 / Number of copies: 4 / Formula: OLA |
---|---|
Molecular weight | Theoretical: 282.461 Da |
Chemical component information | ![]() ChemComp-OLA: |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
![]() | single particle reconstruction |
Aggregation state | particle |
-
Sample preparation
Buffer | pH: 7.5 |
---|---|
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DARK FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
-
Image processing
Startup model | Type of model: PDB ENTRY |
---|---|
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 210603 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |