4M49

Lactate Dehydrogenase A in complex with a substituted pyrazine inhibitor compound 18

PDB DOI: https://doi.org/10.2210/pdb4M49/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2013-08-06 Released: 2013-09-04
Deposition Author(s): Eigenbrot, C., Ultsch, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.05 Å
R-Value Free: 0.224
R-Value Work: 0.171
R-Value Observed: 0.172

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 2.0 of the entry. See complete history.

Literature

Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase.

Fauber, B.P., Dragovich, P.S., Chen, J., Corson, L.B., Ding, C.Z., Eigenbrot, C., Giannetti, A.M., Hunsaker, T., Labadie, S., Liu, Y., Liu, Y., Malek, S., Peterson, D., Pitts, K., Sideris, S., Ultsch, M., Vanderporten, E., Wang, J., Wei, B., Yen, I., Yue, Q.

(2013) Bioorg Med Chem Lett 23: 5533-5539

PubMed: 24012183 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2013.08.060
Primary Citation of Related Structures:
4M49

PubMed Abstract:
A 2-amino-5-aryl-pyrazine was identified as an inhibitor of human lactate dehydrogenase A (LDHA) via a biochemical screening campaign. Biochemical and biophysical experiments demonstrated that the compound specifically interacted with human LDHA. Structural variation of the screening hit resulted in improvements in LDHA biochemical inhibition and pharmacokinetic properties. A crystal structure of an improved compound bound to human LDHA was also obtained and it explained many of the observed structure-activity relationships.

Organizational Affiliation

Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].

Macromolecule Content

Total Structure Weight: 151.28 kDa
Atom Count: 11,248
Modelled Residue Count: 1,324
Deposited Residue Count: 1,324
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
L-lactate dehydrogenase A chain	A, B, C, D	331	Homo sapiens	Mutation(s): 0 Gene Names: LDHA, PIG19 EC: 1.1.1.27
UniProt & NIH Common Fund Data Resources
Find proteins for P00338 (Homo sapiens) Explore P00338 Go to UniProtKB: P00338
PHAROS: P00338 GTEx: ENSG00000134333
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00338
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAI Query on NAI Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain I [auth B] SDF format, chain L [auth C] SDF format, chain P [auth D] MOL2 format, chain E [auth A] MOL2 format, chain I [auth B] MOL2 format, chain L [auth C] MOL2 format, chain P [auth D] mmCIF format, chain E [auth A] mmCIF format, chain I [auth B] mmCIF format, chain L [auth C] mmCIF format, chain P [auth D]	E [auth A], I [auth B], L [auth C], P [auth D]	1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE C₂₁ H₂₉ N₇ O₁₄ P₂ BOPGDPNILDQYTO-NNYOXOHSSA-N		Interactions Focus chain E [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain P [auth D] Interactions & Density Focus chain E [auth A] Focus chain I [auth B] Focus chain L [auth C] Focus chain P [auth D]
22Y Query on 22Y Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain N [auth C] SDF format, chain Q [auth D] MOL2 format, chain G [auth A] MOL2 format, chain N [auth C] MOL2 format, chain Q [auth D] mmCIF format, chain G [auth A] mmCIF format, chain N [auth C] mmCIF format, chain Q [auth D]	G [auth A], N [auth C], Q [auth D]	3-(5-amino-6-{[(1R)-1-phenylethyl]amino}pyrazin-2-yl)-4-chlorobenzoic acid C₁₉ H₁₇ Cl N₄ O₂ NKUNTWSMUIPKSU-LLVKDONJSA-N		Interactions Focus chain G [auth A] Focus chain N [auth C] Focus chain Q [auth D] Interactions & Density Focus chain G [auth A] Focus chain N [auth C] Focus chain Q [auth D]
EPE Query on EPE Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain J [auth B] SDF format, chain M [auth C] MOL2 format, chain F [auth A] MOL2 format, chain J [auth B] MOL2 format, chain M [auth C] mmCIF format, chain F [auth A] mmCIF format, chain J [auth B] mmCIF format, chain M [auth C]	F [auth A], J [auth B], M [auth C]	4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID C₈ H₁₈ N₂ O₄ S JKMHFZQWWAIEOD-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain J [auth B] Focus chain M [auth C] Interactions & Density Focus chain F [auth A] Focus chain J [auth B] Focus chain M [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain O [auth C] SDF format, chain R [auth D] MOL2 format, chain H [auth A] MOL2 format, chain O [auth C] MOL2 format, chain R [auth D] mmCIF format, chain H [auth A] mmCIF format, chain O [auth C] mmCIF format, chain R [auth D]	H [auth A], O [auth C], R [auth D]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain H [auth A] Focus chain O [auth C] Focus chain R [auth D] Interactions & Density Focus chain H [auth A] Focus chain O [auth C] Focus chain R [auth D]
LAC Query on LAC Download Ideal Coordinates CCD File SDF format, chain K [auth B] MOL2 format, chain K [auth B] mmCIF format, chain K [auth B]	K [auth B]	LACTIC ACID C₃ H₆ O₃ JVTAAEKCZFNVCJ-UWTATZPHSA-N		Interactions Focus chain K [auth B] Interactions & Density Focus chain K [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
22Y	BindingDB: 4M49	Kd: 5000 (nM) from 1 assay(s)
22Y	BindingDB: 4M49	IC50: 2000 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.05 Å
R-Value Free: 0.224
R-Value Work: 0.171
R-Value Observed: 0.172
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 168.379	α = 90
b = 81.821	β = 117.65
c = 120.665	γ = 90

Software Package:

Software Name	Purpose
BOS	data collection
PHASER	phasing
PHENIX	refinement
HKL-2000	data reduction
SCALEPACK	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-09-04

Deposition Author(s):

Eigenbrot, C.

Ultsch, M.

Revision History (Full details and data files)

Version 1.0: 2013-09-04
Type: Initial release
Version 1.1: 2013-10-02
Changes: Database references
Version 1.2: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description
Version 2.0: 2023-11-15
Changes: Atomic model, Data collection

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Help and Resources

4M49

Lactate Dehydrogenase A in complex with a substituted pyrazine inhibitor compound 18

Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)