[English] 日本語
Yorodumi
- PDB-9b4g: Structure of inhibitor-bound human PSS1 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9b4g
TitleStructure of inhibitor-bound human PSS1
ComponentsPhosphatidylserine synthase 1
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


L-serine-phosphatidylethanolamine phosphatidyltransferase / L-serine-phosphatidylethanolamine phosphatidyltransferase activity / L-serine-phosphatidylcholine phosphatidyltransferase activity / Synthesis of PS / phosphatidylserine biosynthetic process / transferase activity / endoplasmic reticulum membrane / membrane
Similarity search - Function
Phosphatidyl serine synthase / Phosphatidyl serine synthase
Similarity search - Domain/homology
Chem-6OU / : / : / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / Chem-P5S / Phosphatidylserine synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.87 Å
AuthorsLong, T. / Li, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM135343 United States
CitationJournal: Cell / Year: 2024
Title: Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
Authors: Tao Long / Dongyu Li / Goncalo Vale / Yaoyukun Jiang / Philip Schmiege / Zhongyue J Yang / Jeffrey G McDonald / Xiaochun Li /
Abstract: In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). ...In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1), the LMS-causing Pro269Ser mutant (PSS1), and PSS1 in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.
History
DepositionMar 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Phosphatidylserine synthase 1
B: Phosphatidylserine synthase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,34318
Polymers96,7192
Non-polymers10,62416
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

-
Components

-
Protein , 1 types, 2 molecules AB

#1: Protein Phosphatidylserine synthase 1 / PSS-1 / PtdSer synthase 1 / Serine-exchange enzyme I


Mass: 48359.551 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTDSS1, KIAA0024, PSSA / Production host: Homo sapiens (human)
References: UniProt: P48651, L-serine-phosphatidylethanolamine phosphatidyltransferase

-
Non-polymers , 7 types, 30 molecules

#2: Chemical
ChemComp-P5S / O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / phosphatidyl serine


Mass: 792.075 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO10P
#3: Chemical
ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate


Mass: 760.076 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#4: Chemical ChemComp-A1AIS / (2R)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dihexadecanoate


Mass: 811.032 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H79O13P
#5: Chemical ChemComp-6OU / [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#7: Chemical ChemComp-A1AIT / (7P)-7-[(4S)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]phenyl}-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1,3-benzoxazol-2(3H)-one


Mass: 638.465 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H18F8N4O4 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: inhibitor-bound human PSS1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

-
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 FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

-
Processing

EM softwareName: PHENIX / Version: 1.17_3644: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 271650 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0057276
ELECTRON MICROSCOPYf_angle_d0.6479855
ELECTRON MICROSCOPYf_dihedral_angle_d21.3292557
ELECTRON MICROSCOPYf_chiral_restr0.041026
ELECTRON MICROSCOPYf_plane_restr0.0041138

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbjlvh1.pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more