[English] 日本語
Yorodumi
- PDB-9bi8: Crystal structure of inhibitor GNE-6893 bound to HPK1 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9bi8
TitleCrystal structure of inhibitor GNE-6893 bound to HPK1
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsSIGNALING PROTEIN / HPK1 / MAP4K1 / cancer / pharmacology / kinase / inhibitor
Function / homology
Function and homology information


MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / protein phosphorylation ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / membrane / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. ...Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / : / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsKiefer, J.R. / Tellis, J.C. / Chan, B.K. / Wang, W. / Wu, P. / Choo, E.F. / Heffron, T.P. / Wei, B. / Siu, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.
Authors: Tellis, J.C. / Wei, B. / Siu, M. / An, L. / Chan, G.K. / Chen, Y. / Du, X. / Gazzard, L. / Hu, B. / Kiefer, J. / Kakiuchi-Kiyota, S. / Lainchbury, M. / Linehan, J.L. / Luo, X. / Malhotra, S. ...Authors: Tellis, J.C. / Wei, B. / Siu, M. / An, L. / Chan, G.K. / Chen, Y. / Du, X. / Gazzard, L. / Hu, B. / Kiefer, J. / Kakiuchi-Kiyota, S. / Lainchbury, M. / Linehan, J.L. / Luo, X. / Malhotra, S. / Mendonca, R. / Pang, J. / Ran, Y. / Sethuraman, V. / Seward, E. / Sneeringer, C. / Su, D. / Wang, W. / Wu, P. / Moffat, J.G. / Heffron, T.P. / Choo, E.F. / Chan, B.K.
History
DepositionApr 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase kinase 1
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,0456
Polymers70,0372
Non-polymers1,0084
Water2,612145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5160 Å2
ΔGint-55 kcal/mol
Surface area26800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.300, 75.860, 86.870
Angle α, β, γ (deg.)90.000, 98.400, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb

-
Components

#1: Protein Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEK kinase kinase 1 / MEKKK 1


Mass: 35018.434 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1APL / (3R,4S)-4-methyloxolan-3-yl [(6P)-8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]carbamate


Mass: 453.466 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24FN5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.11 Å3/Da / Density % sol: 41.66 %
Crystal growTemperature: 292 K / Method: vapor diffusion
Details: 0.1 M Tris-HCl, pH 8.5, 0.25 M sodium tartrate and 12% PEG 8000

-
Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.028→44.814 Å / Num. obs: 65504 / % possible obs: 89.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 31.96 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.061 / Rrim(I) all: 0.113 / Net I/σ(I): 6.7
Reflection shellResolution: 2.028→2.035 Å / % possible obs: 54.5 % / Redundancy: 2.5 % / Rmerge(I) obs: 1.696 / Num. measured all: 531 / Num. unique obs: 214 / Rpim(I) all: 1.347 / Rrim(I) all: 2.184 / Net I/σ(I) obs: 0.6

-
Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→34.7 Å / SU ML: 0.2938 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.877
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2711 2165 5.02 %
Rwork0.1999 40980 -
obs0.2033 43145 79.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.5 Å2
Refinement stepCycle: LAST / Resolution: 2.25→34.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4491 0 71 145 4707
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00334666
X-RAY DIFFRACTIONf_angle_d0.54486336
X-RAY DIFFRACTIONf_chiral_restr0.0388708
X-RAY DIFFRACTIONf_plane_restr0.004802
X-RAY DIFFRACTIONf_dihedral_angle_d4.3123628
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.310.3808760.26511691X-RAY DIFFRACTION49.29
2.31-2.360.38141100.25171891X-RAY DIFFRACTION55.44
2.36-2.430.2808980.25872029X-RAY DIFFRACTION59.1
2.43-2.50.3061020.2412191X-RAY DIFFRACTION63.96
2.5-2.580.32781450.24192302X-RAY DIFFRACTION67.56
2.58-2.670.2791380.25222506X-RAY DIFFRACTION72.9
2.67-2.780.28971610.2482632X-RAY DIFFRACTION78.41
2.78-2.90.34011480.24622830X-RAY DIFFRACTION82.45
2.9-3.060.31331520.23593191X-RAY DIFFRACTION91.97
3.06-3.250.31861530.22743309X-RAY DIFFRACTION96.49
3.25-3.50.30821790.20383321X-RAY DIFFRACTION96.74
3.5-3.850.25221970.18133272X-RAY DIFFRACTION96.09
3.85-4.410.2151500.1613193X-RAY DIFFRACTION93.04
4.41-5.550.23141880.15333336X-RAY DIFFRACTION97.86
5.55-34.70.23031680.18033286X-RAY DIFFRACTION96
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.678223725147-0.259977501847-0.05714918348281.277894587960.3569108895050.6312347370920.01797391334920.01257802284170.304236603507-0.15784718983-0.0325621789334-0.222268579847-0.03592226071410.0972655242558-0.04756868156280.1327964367230.0109419582386-0.02142078617470.2087732106120.05499654141490.31915307428952.13648906434.2914324374232.9625306794
2-0.0459090289416-0.1404799588440.17903645645-0.1663965555730.490764150293-0.0459513003796-0.02173994548810.00626168831725-0.0654732533595-0.134637716256-0.04837833165940.0772645649113-0.06861877803260.0433918797577-7.42684554034E-50.3162307944470.01159869619660.03179257658940.2811813905940.005439468468980.22576718752453.6046852859-11.116649007219.3694727149
30.497024980095-0.0979839191232-0.3528291600591.07131948824-0.5065054256420.2292993833090.002638916161240.05931894797440.0148877776066-0.0398454358024-0.1977885400670.1538283775820.158683967886-0.188095221259-0.04211137124560.1523711671840.0318317090625-0.03609848606160.249863771696-0.06053128678910.19731792009335.7996785998-11.7497850937.0167829038
40.201870035351-0.1081838632440.1382693081840.129149716788-0.0196641333250.318315819793-0.0192000269625-0.236027773218-0.129264997184-0.1357836707190.1110141154980.1528213093030.3015211274830.1590695216220.08182322792060.429382105980.16283430034-0.07412124356420.4404423782340.09326258953490.33836064179269.6887805691-45.052288656525.0733740808
50.65468684102-0.0838670172561-0.162940745911-0.2298835305050.2666086913910.823503618459-0.0801611836775-0.145031038075-0.0977460633516-0.1458197800220.0955653432478-0.1303439619060.489143736235-0.0047163671974-0.0001603146279060.331005284295-0.008175118489790.02130107764990.2176868440280.005451307172770.21922966745461.2790351596-39.620026072814.0064588547
6-0.240002097559-0.229856675103-0.3374590801760.0505749276147-0.1662958898440.108821241546-0.0795610447694-0.0467581017562-0.113692166661-0.08088535232090.1715988698820.0787669235285-0.09189737870630.01891443122492.87815821349E-60.299200226799-0.005537490827640.05158961538840.223904571501-0.01280805731570.29453752076552.3616326977-25.694949128123.0508343263
70.371073281740.1137110519070.04280641374080.442515726606-0.1136125782810.2698104853090.2678917345830.05866921465650.220872505268-0.128876993738-0.126120224301-0.0302201960698-0.2983658590670.08286138545920.1427971307690.4663309020620.008766552427040.1341791432490.2223583181737.56904962519E-50.24670845550660.6623342106-20.67741055790.0620807984259
80.108331514647-0.1572425215650.1353235237730.2746553131370.2125474609170.433250703510.04097742215110.1333582109810.251039779787-0.623894470532-0.00842092762289-0.343319092860.0545758534832-0.0246119563124-0.009974210235960.3777620916830.032209373531-0.04882893592780.2471453077630.01796031197280.21056177300961.6072434307-35.0785710194-3.59624135634
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 6 through 150 )AA6 - 1501 - 145
22chain 'A' and (resid 151 through 193 )AA151 - 193146 - 188
33chain 'A' and (resid 194 through 295 )AA194 - 295189 - 290
44chain 'B' and (resid 6 through 41 )BB6 - 411 - 36
55chain 'B' and (resid 42 through 150 )BB42 - 15037 - 145
66chain 'B' and (resid 151 through 193 )BB151 - 193146 - 188
77chain 'B' and (resid 194 through 254 )BB194 - 254189 - 249
88chain 'B' and (resid 255 through 295 )BB255 - 295250 - 290

+
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://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