[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitleInactivation-mimicking block of the epithelial calcium channel TRPV6.
Journal, issue, pagesSci Adv, Vol. 6, Issue 48, Year 2020
Publish dateNov 27, 2020
AuthorsRajesh Bhardwaj / Sonja Lindinger / Arthur Neuberger / Kirill D Nadezhdin / Appu K Singh / Micael R Cunha / Isabella Derler / Gergely Gyimesi / Jean-Louis Reymond / Matthias A Hediger / Christoph Romanin / Alexander I Sobolevsky /
PubMed AbstractEpithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of ...Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo-electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.
External linksSci Adv / PubMed:33246965 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.1 - 4.34 Å
Structure data

22662

7k4a

EMDB-22662, PDB-7k4a:
Cryo-EM structure of human TRPV6 in the open state
Method: EM (single particle) / Resolution: 3.26 Å

22663

7k4b

EMDB-22663, PDB-7k4b:
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor cis-22a
Method: EM (single particle) / Resolution: 3.1 Å

22664

7k4c

EMDB-22664, PDB-7k4c:
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor Br-cis-22a
Method: EM (single particle) / Resolution: 3.78 Å

22665

7k4d

EMDB-22665, PDB-7k4d:
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor 3OG
Method: EM (single particle) / Resolution: 3.66 Å

22666

7k4e

EMDB-22666, PDB-7k4e:
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor 30
Method: EM (single particle) / Resolution: 4.34 Å

22667

7k4f

EMDB-22667, PDB-7k4f:
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor 31
Method: EM (single particle) / Resolution: 3.75 Å

PDB-7d2k:
Crystal structure of rat TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor Br-cis-22a
Method: X-RAY DIFFRACTION / Resolution: 3.698 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-GQC:
1-(5-bromanylpyridin-3-yl)-4-[4-(3-methylphenyl)cyclohexyl]piperazin-4-ium

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-VUG:
1-[cis-4-(3-methylphenyl)cyclohexyl]-4-(pyridin-3-yl)piperazine

ChemComp-81F:
1-(5-bromopyridin-3-yl)-4-[cis-4-(3-methylphenyl)cyclohexyl]piperazine

ChemComp-VUM:
5-[(4-{trans-4-hydroxy-4-[3-(trifluoromethyl)phenyl]cyclohexyl}piperazin-1-yl)methyl]pyridin-2(1H)-one

ChemComp-VUJ:
5-({4-[(1R,4S)-3'-methyl[1,2,3,4-tetrahydro[1,1'-biphenyl]]-4-yl]piperazin-1-yl}methyl)pyridin-2(1H)-one

ChemComp-5GK:
5-[(4-{cis-4-[3-(trifluoromethyl)phenyl]cyclohexyl}piperazin-1-yl)methyl]pyridin-2(1H)-one

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN/INHIBITOR / Ion channels / TRP channels / Membrane proteins / TRANSPORT PROTEIN-INHIBITOR complex / MEMBRANE PROTEIN / TRPV6 / ion channel / open state / MEMBRANE PROTEIN/INHIBITOR / inhibitor / MEMBRANE PROTEIN-INHIBITOR complex

+
About Yorodumi Papers

-
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://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 Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more