4LOP

Structural basis of autoactivation of p38 alpha induced by TAB1 (Tetragonal crystal form)

PDB DOI: https://doi.org/10.2210/pdb4LOP/pdb

Classification: TRANSFERASE
Organism(s): Mus musculus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2013-07-13 Released: 2013-08-21
Deposition Author(s): Chaikuad, A., DeNicola, G.F., Krojer, T., Allerston, C.K., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Marber, M.S., Knapp, S., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.05 ?
R-Value Free: 0.188
R-Value Work: 0.148
R-Value Observed: 0.150

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Mechanism and consequence of the autoactivation of p38 alpha mitogen-activated protein kinase promoted by TAB1.

De Nicola, G.F., Martin, E.D., Chaikuad, A., Bassi, R., Clark, J., Martino, L., Verma, S., Sicard, P., Tata, R., Atkinson, R.A., Knapp, S., Conte, M.R., Marber, M.S.

(2013) Nat Struct Mol Biol 20: 1182-1190

PubMed: 24037507 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/nsmb.2668
Primary Citation of Related Structures:
4LOO, 4LOP, 4LOQ

PubMed Abstract:
p38α mitogen-activated protein kinase (p38α) is activated by a variety of mechanisms, including autophosphorylation initiated by TGFβ-activated kinase 1 binding protein 1 (TAB1) during myocardial ischemia and other stresses. Chemical-genetic approaches and coexpression in mammalian, bacterial and cell-free systems revealed that mouse p38α autophosphorylation occurs in cis by direct interaction with TAB1(371-416). In isolated rat cardiac myocytes and perfused mouse hearts, TAT-TAB1(371-416) rapidly activates p38 and profoundly perturbs function. Crystal structures and characterization in solution revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe. TAB1 binding stabilizes active p38α and induces rearrangements within the activation segment by helical extension of the Thr-Gly-Tyr motif, allowing autophosphorylation in cis. Interference with p38α recognition by TAB1 abolishes its cardiac toxicity. Such intervention could potentially circumvent the drawbacks of clinical pharmacological inhibitors of p38 catalytic activity.

Organizational Affiliation

King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.

Macromolecule Content

Total Structure Weight: 180.58 kDa
Atom Count: 12,902
Modelled Residue Count: 1,472
Deposited Residue Count: 1,560
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Mitogen-activated protein kinase 14	A, B, C, D	361	Mus musculus	Mutation(s): 0 Gene Names: MAPK14, Crk1, Csbp1, Csbp2 EC: 2.7.11.24
UniProt
Find proteins for P47811 (Mus musculus) Explore P47811 Go to UniProtKB: P47811
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P47811
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
TGF-beta-activated kinase 1 and MAP3K7-binding protein 1	E [auth K], F [auth L], G [auth M], H [auth N]	29	Mus musculus	Mutation(s): 0
UniProt
Find proteins for Q8CF89 (Mus musculus) Explore Q8CF89 Go to UniProtKB: Q8CF89
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8CF89
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
SB4 Query on SB4 Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain N [auth B] SDF format, chain S [auth C] SDF format, chain X [auth D] MOL2 format, chain I [auth A] MOL2 format, chain N [auth B] MOL2 format, chain S [auth C] MOL2 format, chain X [auth D] mmCIF format, chain I [auth A] mmCIF format, chain N [auth B] mmCIF format, chain S [auth C] mmCIF format, chain X [auth D]	I [auth A], N [auth B], S [auth C], X [auth D]	4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE C₁₈ H₁₉ F N₆ VSPFURGQAYMVAN-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain N [auth B] Focus chain S [auth C] Focus chain X [auth D] Interactions & Density Focus chain I [auth A] Focus chain N [auth B] Focus chain S [auth C] Focus chain X [auth D]
TLA Query on TLA Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain Y [auth D] MOL2 format, chain J [auth A] MOL2 format, chain Y [auth D] mmCIF format, chain J [auth A] mmCIF format, chain Y [auth D]	J [auth A], Y [auth D]	L(+)-TARTARIC ACID C₄ H₆ O₆ FEWJPZIEWOKRBE-JCYAYHJZSA-N		Interactions Focus chain J [auth A] Focus chain Y [auth D] Interactions & Density Focus chain J [auth A] Focus chain Y [auth D]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain AA [auth D] SDF format, chain BA [auth D] SDF format, chain CA [auth D] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain T [auth C] SDF format, chain U [auth C] SDF format, chain V [auth C] SDF format, chain W [auth C] SDF format, chain Z [auth D] MOL2 format, chain AA [auth D] MOL2 format, chain BA [auth D] MOL2 format, chain CA [auth D] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain T [auth C] MOL2 format, chain U [auth C] MOL2 format, chain V [auth C] MOL2 format, chain W [auth C] MOL2 format, chain Z [auth D] mmCIF format, chain AA [auth D] mmCIF format, chain BA [auth D] mmCIF format, chain CA [auth D] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain T [auth C] mmCIF format, chain U [auth C] mmCIF format, chain V [auth C] mmCIF format, chain W [auth C] mmCIF format, chain Z [auth D]	AA [auth D] BA [auth D] CA [auth D] K [auth A] L [auth A] AA [auth D], BA [auth D], CA [auth D], K [auth A], L [auth A], M [auth A], O [auth B], P [auth B], Q [auth B], R [auth B], T [auth C], U [auth C], V [auth C], W [auth C], Z [auth D]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AA [auth D] Focus chain BA [auth D] Focus chain CA [auth D] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain T [auth C] Focus chain U [auth C] Focus chain V [auth C] Focus chain W [auth C] Focus chain Z [auth D] Interactions & Density Focus chain AA [auth D] Focus chain BA [auth D] Focus chain CA [auth D] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain T [auth C] Focus chain U [auth C] Focus chain V [auth C] Focus chain W [auth C] Focus chain Z [auth D]

Binding Affinity Annotations
ID	Source	Binding Affinity
SB4	PDBBind: 4LOP	Kd: 7 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.05 ?
R-Value Free: 0.188
R-Value Work: 0.148
R-Value Observed: 0.150
Space Group: P 4₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 86.54	α = 90
b = 86.54	β = 90
c = 226.92	γ = 90

Software Package:

Software Name	Purpose
GDA	data collection
PHASER	phasing
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-08-21

Deposition Author(s):

Structural Genomics Consortium (SGC)

Revision History (Full details and data files)

Version 1.0: 2013-08-21
Type: Initial release
Version 1.1: 2013-09-11
Changes: Database references
Version 1.2: 2013-10-02
Changes: Database references
Version 1.3: 2013-10-23
Changes: Database references
Version 1.4: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description

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Help and Resources

4LOP

Structural basis of autoactivation of p38 alpha induced by TAB1 (Tetragonal crystal form)

Mechanism and consequence of the autoactivation of p38 alpha mitogen-activated protein kinase promoted by TAB1.

Entity ID: 1

UniProt

Entity Groups

Sequence Annotations

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Entity ID: 2