[English] 日本語
Yorodumi
- PDB-4hw2: Discovery of potent Mcl-1 inhibitors using fragment-based methods... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4hw2
TitleDiscovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / regulation of apoptosis / maintenance of viability / APOPTOSIS / APOPTOSIS-INHIBITOR complex
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / nucleoplasm / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / BCL (B-Cell lymphoma); contains BH1, BH2 regions ...Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 / Bcl2-like / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-19H / TRIETHYLENE GLYCOL / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsZhao, B.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.
Authors: Friberg, A. / Vigil, D. / Zhao, B. / Daniels, R.N. / Burke, J.P. / Garcia-Barrantes, P.M. / Camper, D. / Chauder, B.A. / Lee, T. / Olejniczak, E.T. / Fesik, S.W.
History
DepositionNov 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 9, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Induced myeloid leukemia cell differentiation protein Mcl-1
F: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,83016
Polymers104,9636
Non-polymers2,86610
Water00
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,0363
Polymers17,4941
Non-polymers5422
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2495
Polymers17,4941
Non-polymers7554
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8862
Polymers17,4941
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8862
Polymers17,4941
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8862
Polymers17,4941
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8862
Polymers17,4941
Non-polymers3921
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)121.997, 134.327, 62.043
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

-
Components

#1: Protein
Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 17493.906 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Plasmid: pDEST-HisMBP / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus (DE3)-RIL / References: UniProt: Q07820
#2: Chemical
ChemComp-19H / 6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1H-indole-2-carboxylic acid


Mass: 392.276 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C20H19Cl2NO3
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H14O4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.42 Å3/Da / Density % sol: 49.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 30% PEG3350, 0.2M MgCl2, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07816 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jul 11, 2012
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07816 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. all: 25224 / Num. obs: 25097 / % possible obs: 97.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 4.1 Å2 / Rmerge(I) obs: 0.047 / Rsym value: 0.057 / Net I/σ(I): 21.7
Reflection shellResolution: 2.8→2.85 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.411 / Mean I/σ(I) obs: 3 / Num. unique all: 1223 / Rsym value: 0.297 / % possible all: 95

-
Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
CNS1.3refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→30 Å / Isotropic thermal model: Anisotropic / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.2452 2490 RANDOM
Rwork0.2169 --
all0.2169 25224 -
obs0.2169 25097 -
Displacement parametersBiso mean: 51.3 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2---0.02 Å20 Å2
3---0.25 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.35 Å
Luzzati d res low-5 Å
Luzzati sigma a0.54 Å0.45 Å
Refinement stepCycle: LAST / Resolution: 2.8→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7186 0 190 0 7376
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.024
X-RAY DIFFRACTIONc_angle_d1.9
LS refinement shellResolution: 2.8→2.9 Å
RfactorNum. reflection% reflection
Rfree0.3633 234 -
Rwork0.3151 --
obs-2128 93.3 %

+
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