3ME3

Activator-Bound Structure of Human Pyruvate Kinase M2

PDB DOI: https://doi.org/10.2210/pdb3ME3/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2010-03-31 Released: 2010-04-28
Deposition Author(s): Hong, B., Dimov, S., Tempel, W., Auld, D., Thomas, C., Boxer, M., Jianq, J.-K., Skoumbourdis, A., Min, S., Southall, N., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Weigelt, J., Bochkarev, A., Inglese, J., Park, H., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.95 ?
R-Value Free: 0.262
R-Value Work: 0.219
R-Value Observed: 0.219

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.7 of the entry. See complete history.

Literature

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.

Anastasiou, D., Yu, Y., Israelsen, W.J., Jiang, J.K., Boxer, M.B., Hong, B.S., Tempel, W., Dimov, S., Shen, M., Jha, A., Yang, H., Mattaini, K.R., Metallo, C.M., Fiske, B.P., Courtney, K.D., Malstrom, S., Khan, T.M., Kung, C., Skoumbourdis, A.P., Veith, H., Southall, N., Walsh, M.J., Brimacombe, K.R., Leister, W., Lunt, S.Y., Johnson, Z.R., Yen, K.E., Kunii, K., Davidson, S.M., Christofk, H.R., Austin, C.P., Inglese, J., Harris, M.H., Asara, J.M., Stephanopoulos, G., Salituro, F.G., Jin, S., Dang, L., Auld, D.S., Park, H.W., Cantley, L.C., Thomas, C.J., Vander Heiden, M.G.

(2012) Nat Chem Biol 8: 839-847

PubMed: 22922757 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/nchembio.1060
Primary Citation of Related Structures:
3ME3, 3U2Z

PubMed Abstract:
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

Organizational Affiliation

Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Macromolecule Content

Total Structure Weight: 242.85 kDa
Atom Count: 16,045
Modelled Residue Count: 2,037
Deposited Residue Count: 2,200
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Pyruvate kinase isozymes M1/M2	A, B, C, D	550	Homo sapiens	Mutation(s): 0 Gene Names: PKM2, OIP3, PK2, PK3, PKM EC: 2.7.1.40 (PDB Primary Data), 2.7.11.1 (UniProt), 2.7.10.2 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P14618 (Homo sapiens) Explore P14618 Go to UniProtKB: P14618
PHAROS: P14618 GTEx: ENSG00000067225
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P14618
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
3SZ Query on 3SZ Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain UA [auth D] MOL2 format, chain E [auth A] MOL2 format, chain UA [auth D] mmCIF format, chain E [auth A] mmCIF format, chain UA [auth D]	E [auth A], UA [auth D]	3-{[4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-1,4-diazepan-1-yl]sulfonyl}aniline C₁₉ H₂₃ N₃ O₆ S₂ GMHIOMMKSMSRLY-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain UA [auth D] Interactions & Density Focus chain E [auth A] Focus chain UA [auth D]
FBP Query on FBP Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain HA [auth C] SDF format, chain V [auth B] SDF format, chain VA [auth D] MOL2 format, chain F [auth A] MOL2 format, chain HA [auth C] MOL2 format, chain V [auth B] MOL2 format, chain VA [auth D] mmCIF format, chain F [auth A] mmCIF format, chain HA [auth C] mmCIF format, chain V [auth B] mmCIF format, chain VA [auth D]	F [auth A], HA [auth C], V [auth B], VA [auth D]	1,6-di-O-phosphono-beta-D-fructofuranose C₆ H₁₄ O₁₂ P₂ RNBGYGVWRKECFJ-ARQDHWQXSA-N		Interactions Focus chain F [auth A] Focus chain HA [auth C] Focus chain V [auth B] Focus chain VA [auth D] Interactions & Density Focus chain F [auth A] Focus chain HA [auth C] Focus chain V [auth B] Focus chain VA [auth D]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain WA [auth D] SDF format, chain G [auth A] SDF format, chain IA [auth C] SDF format, chain W [auth B] MOL2 format, chain WA [auth D] MOL2 format, chain G [auth A] MOL2 format, chain IA [auth C] MOL2 format, chain W [auth B] mmCIF format, chain WA [auth D] mmCIF format, chain G [auth A] mmCIF format, chain IA [auth C] mmCIF format, chain W [auth B]	G [auth A], IA [auth C], W [auth B], WA [auth D]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain G [auth A] Focus chain IA [auth C] Focus chain W [auth B] Focus chain WA [auth D] Interactions & Density Focus chain G [auth A] Focus chain IA [auth C] Focus chain W [auth B] Focus chain WA [auth D]
UNX Query on UNX Download Ideal Coordinates CCD File SDF format, chain CA [auth B] SDF format, chain FA [auth B] SDF format, chain GA [auth B] SDF format, chain H [auth A] SDF format, chain K [auth A] SDF format, chain KA [auth C] SDF format, chain L [auth A] SDF format, chain LA [auth C] SDF format, chain M [auth A] SDF format, chain MA [auth C] SDF format, chain NA [auth C] SDF format, chain P [auth A] SDF format, chain R [auth A] SDF format, chain RA [auth C] SDF format, chain S [auth A] SDF format, chain TA [auth C] SDF format, chain U [auth A] SDF format, chain AA [auth B] SDF format, chain AB [auth D] SDF format, chain BA [auth B] SDF format, chain BB [auth D] SDF format, chain CB [auth D] SDF format, chain DA [auth B] SDF format, chain DB [auth D] SDF format, chain EA [auth B] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain JA [auth C] SDF format, chain N [auth A] SDF format, chain O [auth A] SDF format, chain OA [auth C] SDF format, chain PA [auth C] SDF format, chain Q [auth A] SDF format, chain QA [auth C] SDF format, chain SA [auth C] SDF format, chain T [auth A] SDF format, chain X [auth B] SDF format, chain XA [auth D] SDF format, chain Y [auth B] SDF format, chain YA [auth D] SDF format, chain Z [auth B] SDF format, chain ZA [auth D] MOL2 format, chain CA [auth B] MOL2 format, chain FA [auth B] MOL2 format, chain GA [auth B] MOL2 format, chain H [auth A] MOL2 format, chain K [auth A] MOL2 format, chain KA [auth C] MOL2 format, chain L [auth A] MOL2 format, chain LA [auth C] MOL2 format, chain M [auth A] MOL2 format, chain MA [auth C] MOL2 format, chain NA [auth C] MOL2 format, chain P [auth A] MOL2 format, chain R [auth A] MOL2 format, chain RA [auth C] MOL2 format, chain S [auth A] MOL2 format, chain TA [auth C] MOL2 format, chain U [auth A] MOL2 format, chain AA [auth B] MOL2 format, chain AB [auth D] MOL2 format, chain BA [auth B] MOL2 format, chain BB [auth D] MOL2 format, chain CB [auth D] MOL2 format, chain DA [auth B] MOL2 format, chain DB [auth D] MOL2 format, chain EA [auth B] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain JA [auth C] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] MOL2 format, chain OA [auth C] MOL2 format, chain PA [auth C] MOL2 format, chain Q [auth A] MOL2 format, chain QA [auth C] MOL2 format, chain SA [auth C] MOL2 format, chain T [auth A] MOL2 format, chain X [auth B] MOL2 format, chain XA [auth D] MOL2 format, chain Y [auth B] MOL2 format, chain YA [auth D] MOL2 format, chain Z [auth B] MOL2 format, chain ZA [auth D] mmCIF format, chain CA [auth B] mmCIF format, chain FA [auth B] mmCIF format, chain GA [auth B] mmCIF format, chain H [auth A] mmCIF format, chain K [auth A] mmCIF format, chain KA [auth C] mmCIF format, chain L [auth A] mmCIF format, chain LA [auth C] mmCIF format, chain M [auth A] mmCIF format, chain MA [auth C] mmCIF format, chain NA [auth C] mmCIF format, chain P [auth A] mmCIF format, chain R [auth A] mmCIF format, chain RA [auth C] mmCIF format, chain S [auth A] mmCIF format, chain TA [auth C] mmCIF format, chain U [auth A] mmCIF format, chain AA [auth B] mmCIF format, chain AB [auth D] mmCIF format, chain BA [auth B] mmCIF format, chain BB [auth D] mmCIF format, chain CB [auth D] mmCIF format, chain DA [auth B] mmCIF format, chain DB [auth D] mmCIF format, chain EA [auth B] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain JA [auth C] mmCIF format, chain N [auth A] mmCIF format, chain O [auth A] mmCIF format, chain OA [auth C] mmCIF format, chain PA [auth C] mmCIF format, chain Q [auth A] mmCIF format, chain QA [auth C] mmCIF format, chain SA [auth C] mmCIF format, chain T [auth A] mmCIF format, chain X [auth B] mmCIF format, chain XA [auth D] mmCIF format, chain Y [auth B] mmCIF format, chain YA [auth D] mmCIF format, chain Z [auth B] mmCIF format, chain ZA [auth D]	AA [auth B] AB [auth D] BA [auth B] BB [auth D] CA [auth B] AA [auth B], AB [auth D], BA [auth B], BB [auth D], CA [auth B], CB [auth D], DA [auth B], DB [auth D], EA [auth B], FA [auth B], GA [auth B], H [auth A], I [auth A], J [auth A], JA [auth C], K [auth A], KA [auth C], L [auth A], LA [auth C], M [auth A], MA [auth C], N [auth A], NA [auth C], O [auth A], OA [auth C], P [auth A], PA [auth C], Q [auth A], QA [auth C], R [auth A], RA [auth C], S [auth A], SA [auth C], T [auth A], TA [auth C], U [auth A], X [auth B], XA [auth D], Y [auth B], YA [auth D], Z [auth B], ZA [auth D]	UNKNOWN ATOM OR ION X		Interactions Focus chain AA [auth B] Focus chain AB [auth D] Focus chain BA [auth B] Focus chain BB [auth D] Focus chain CA [auth B] Focus chain CB [auth D] Focus chain DA [auth B] Focus chain DB [auth D] Focus chain EA [auth B] Focus chain FA [auth B] Focus chain GA [auth B] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain KA [auth C] Focus chain L [auth A] Focus chain LA [auth C] Focus chain M [auth A] Focus chain MA [auth C] Focus chain N [auth A] Focus chain NA [auth C] Focus chain O [auth A] Focus chain OA [auth C] Focus chain P [auth A] Focus chain PA [auth C] Focus chain Q [auth A] Focus chain QA [auth C] Focus chain R [auth A] Focus chain RA [auth C] Focus chain S [auth A] Focus chain SA [auth C] Focus chain T [auth A] Focus chain TA [auth C] Focus chain U [auth A] Focus chain X [auth B] Focus chain XA [auth D] Focus chain Y [auth B] Focus chain YA [auth D] Focus chain Z [auth B] Focus chain ZA [auth D] Interactions & Density Focus chain AA [auth B] Focus chain AB [auth D] Focus chain BA [auth B] Focus chain BB [auth D] Focus chain CA [auth B] Focus chain CB [auth D] Focus chain DA [auth B] Focus chain DB [auth D] Focus chain EA [auth B] Focus chain FA [auth B] Focus chain GA [auth B] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain KA [auth C] Focus chain L [auth A] Focus chain LA [auth C] Focus chain M [auth A] Focus chain MA [auth C] Focus chain N [auth A] Focus chain NA [auth C] Focus chain O [auth A] Focus chain OA [auth C] Focus chain P [auth A] Focus chain PA [auth C] Focus chain Q [auth A] Focus chain QA [auth C] Focus chain R [auth A] Focus chain RA [auth C] Focus chain S [auth A] Focus chain SA [auth C] Focus chain T [auth A] Focus chain TA [auth C] Focus chain U [auth A] Focus chain X [auth B] Focus chain XA [auth D] Focus chain Y [auth B] Focus chain YA [auth D] Focus chain Z [auth B] Focus chain ZA [auth D]

Binding Affinity Annotations
ID	Source	Binding Affinity
3SZ	BindingDB: 3ME3	EC50: 38 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.95 ?
R-Value Free: 0.262
R-Value Work: 0.219
R-Value Observed: 0.219
Space Group: P 1 2₁ 1
Diffraction Data: https://doi.org/10.18430/m33me3

Unit Cell:

Length ( ? )	Angle ( ? )
a = 80.882	α = 90
b = 152.564	β = 103.17
c = 93.036	γ = 90

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
StructureStudio	data collection
HKL-2000	data reduction
HKL-2000	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-04-28

Deposition Author(s):

Structural Genomics Consortium (SGC)

Revision History (Full details and data files)

Version 1.0: 2010-04-28
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2012-09-12
Changes: Database references
Version 1.3: 2012-11-07
Changes: Database references
Version 1.4: 2013-01-02
Changes: Database references
Version 1.5: 2017-11-08
Changes: Refinement description
Version 1.6: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Database references, Derived calculations, Structure summary
Version 1.7: 2023-09-06
Changes: Data collection, Database references, Refinement description, Structure summary