8TBS

Structure of human erythrocyte pyruvate kinase in complex with an allosteric activator AG-946


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Design of AG-946, a Pyruvate Kinase Activator.

Liu, T.Padyana, A.K.Judd, E.T.Jin, L.Hammoudeh, D.Kung, C.Dang, L.

(2024) ChemMedChem 19: e202300559-e202300559

  • DOI: https://doi.org/10.1002/cmdc.202300559
  • Primary Citation of Related Structures:  
    8TBS, 8TBT, 8TBU

  • PubMed Abstract: 

    Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate to pyruvate and adenosine triphosphate in glycolysis and plays a crucial role in regulating cell metabolism. We describe the structure-based design of AG-946, an activator of PK isoforms, including red blood cell-specific forms of PK (PKR). This was designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency toward PKR while reducing activity against off-targets observed from the original scaffold. AG-946 (1) demonstrated activation of human wild-type PK (half-maximal activation concentration [AC 50 ]=0.005 μM) and a panel of mutated PK proteins (K410E [AC 50 =0.0043 μM] and R510Q [AC 50 =0.0069 μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with 6-(3-methoxybenzyl)-4-methyl-2-(methylsulfinyl)-4,6-dihydro-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PKR, AG-946 was advanced to human clinical trials.


  • Organizational Affiliation

    Ensem Therapeutics, 880 Winter St, Waltham, MA 02451, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pyruvate kinase PKLR
A, B, C, D, E
A, B, C, D, E, F, G, H
544Homo sapiensMutation(s): 0 
Gene Names: PKLRPK1PKL
EC: 2.7.1.40
UniProt & NIH Common Fund Data Resources
Find proteins for P30613 (Homo sapiens)
Explore P30613 
Go to UniProtKB:  P30613
PHAROS:  P30613
GTEx:  ENSG00000143627 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP30613
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HVI (Subject of Investigation/LOI)
Query on HVI

Download Ideal Coordinates CCD File 
DA [auth F],
M [auth B],
MA [auth H],
V [auth D]
6-[(6-aminopyridin-2-yl)methyl]-4-methyl-2-[(1H-pyrazol-3-yl)methyl]-4,6-dihydro-5H-[1,3]thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one
C18 H16 N8 O S
DIUOELXIXSCFCR-UHFFFAOYSA-N
FBP
Query on FBP

Download Ideal Coordinates CCD File 
EA [auth F]
I [auth A]
IA [auth G]
N [auth B]
NA [auth H]
EA [auth F],
I [auth A],
IA [auth G],
N [auth B],
NA [auth H],
R [auth C],
W [auth D],
Z [auth E]
1,6-di-O-phosphono-beta-D-fructofuranose
C6 H14 O12 P2
RNBGYGVWRKECFJ-ARQDHWQXSA-N
PYR
Query on PYR

Download Ideal Coordinates CCD File 
CA [auth E]
HA [auth F]
L [auth A]
LA [auth G]
PA [auth H]
CA [auth E],
HA [auth F],
L [auth A],
LA [auth G],
PA [auth H],
Q [auth B],
U [auth C],
Y [auth D]
PYRUVIC ACID
C3 H4 O3
LCTONWCANYUPML-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
AA [auth E]
FA [auth F]
J [auth A]
JA [auth G]
O [auth B]
AA [auth E],
FA [auth F],
J [auth A],
JA [auth G],
O [auth B],
OA [auth H],
S [auth C],
X [auth D]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
K
Query on K

Download Ideal Coordinates CCD File 
BA [auth E]
GA [auth F]
K [auth A]
KA [auth G]
P [auth B]
BA [auth E],
GA [auth F],
K [auth A],
KA [auth G],
P [auth B],
T [auth C]
POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.32α = 90
b = 122.596β = 90
c = 378.458γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2023-12-27
    Type: Initial release
  • Version 1.1: 2024-03-20
    Changes: Database references