7ECS

Crystal Structure of Aspergillus terreus Glutamate Dehydrogenase (AtGDH) Complexed With Malonate and NADPH

PDB DOI: https://doi.org/10.2210/pdb7ECS/pdb

Classification: OXIDOREDUCTASE
Organism(s): Aspergillus terreus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2021-03-13 Released: 2021-12-08
Deposition Author(s): Godsora, B.K.J., Prakash, P., Punekar, N.S., Bhaumik, P.
Funding Organization(s): Department of Biotechnology (DBT, India)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.74 Å
R-Value Free: 0.163
R-Value Work: 0.139
R-Value Observed: 0.140

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Molecular insights into the inhibition of glutamate dehydrogenase by the dicarboxylic acid metabolites.

Godsora, B.K.J., Prakash, P., Punekar, N.S., Bhaumik, P.

(2022) Proteins 90: 810-823

PubMed: 34748226 Search on PubMed
DOI: https://doi.org/10.1002/prot.26276
Primary Citation of Related Structures:
7ECR, 7ECS, 7ECT

PubMed Abstract:
Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD ⁺ - or NADP ⁺ -dependent reversible conversion of α-ketoglutarate (AKG) to l-glutamate; and thereby connects the carbon and nitrogen metabolism cycles in all living organisms. The function of GDH is extensively regulated by both metabolites (citrate, succinate, etc.) and non-metabolites (ATP, NADH, etc.) but sufficient molecular evidences are lacking to rationalize the inhibitory effects by the metabolites. We have expressed and purified NADP ⁺ -dependent Aspergillus terreus GDH (AtGDH) in recombinant form. Succinate, malonate, maleate, fumarate, and tartrate independently inhibit the activity of AtGDH to different extents. The crystal structures of AtGDH complexed with the dicarboxylic acid metabolites and the coenzyme NADPH have been determined. Although AtGDH structures are not complexed with substrate; surprisingly, they acquire super closed conformation like previously reported for substrate and coenzyme bound catalytically competent Aspergillus niger GDH (AnGDH). These dicarboxylic acid metabolites partially occupy the same binding pocket as substrate; but interact with varying polar interactions and the coenzyme NADPH binds to the Domain-II of AtGDH. The low inhibition potential of tartrate as compared to other dicarboxylic acid metabolites is due to its weaker interactions of carboxylate groups with AtGDH. Our results suggest that the length of carbon skeleton and positioning of the carboxylate groups of inhibitors between two conserved lysine residues at the GDH active site might be the determinants of their inhibitory potency. Molecular details on the dicarboxylic acid metabolites bound AtGDH active site architecture presented here would be applicable to GDHs in general.

Organizational Affiliation

Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.

Macromolecule Content

Total Structure Weight: 152.8 kDa
Atom Count: 12,647
Modelled Residue Count: 1,380
Deposited Residue Count: 1,380
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glutamate dehydrogenase	A, B, C	460	Aspergillus terreus	Mutation(s): 0 Gene Names: gdhA, ATETN484_0007063400
UniProt
Find proteins for T2D1F5 (Aspergillus terreus) Explore T2D1F5 Go to UniProtKB: T2D1F5
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	T2D1F5
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP (Subject of Investigation/LOI) Query on NDP Download Ideal Coordinates CCD File SDF format, chain JA [auth C] SDF format, chain M [auth A] SDF format, chain Y [auth B] MOL2 format, chain JA [auth C] MOL2 format, chain M [auth A] MOL2 format, chain Y [auth B] mmCIF format, chain JA [auth C] mmCIF format, chain M [auth A] mmCIF format, chain Y [auth B]	JA [auth C], M [auth A], Y [auth B]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain JA [auth C] Focus chain M [auth A] Focus chain Y [auth B] Interactions & Density Focus chain JA [auth C] Focus chain M [auth A] Focus chain Y [auth B]
MLI (Subject of Investigation/LOI) Query on MLI Download Ideal Coordinates CCD File SDF format, chain HA [auth C] SDF format, chain IA [auth C] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain W [auth B] SDF format, chain X [auth B] MOL2 format, chain HA [auth C] MOL2 format, chain IA [auth C] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain W [auth B] MOL2 format, chain X [auth B] mmCIF format, chain HA [auth C] mmCIF format, chain IA [auth C] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain W [auth B] mmCIF format, chain X [auth B]	HA [auth C] IA [auth C] K [auth A] L [auth A] W [auth B] HA [auth C], IA [auth C], K [auth A], L [auth A], W [auth B], X [auth B]	MALONATE ION C₃ H₂ O₄ OFOBLEOULBTSOW-UHFFFAOYSA-L		Interactions Focus chain HA [auth C] Focus chain IA [auth C] Focus chain K [auth A] Focus chain L [auth A] Focus chain W [auth B] Focus chain X [auth B] Interactions & Density Focus chain HA [auth C] Focus chain IA [auth C] Focus chain K [auth A] Focus chain L [auth A] Focus chain W [auth B] Focus chain X [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain AA [auth C] SDF format, chain BA [auth C] SDF format, chain CA [auth C] SDF format, chain D [auth A] SDF format, chain DA [auth C] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain FA [auth C] SDF format, chain G [auth A] SDF format, chain GA [auth C] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain N [auth B] 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 S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain V [auth B] SDF format, chain Z [auth C] SDF format, chain EA [auth C] MOL2 format, chain AA [auth C] MOL2 format, chain BA [auth C] MOL2 format, chain CA [auth C] MOL2 format, chain D [auth A] MOL2 format, chain DA [auth C] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain FA [auth C] MOL2 format, chain G [auth A] MOL2 format, chain GA [auth C] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain N [auth B] 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 S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] MOL2 format, chain Z [auth C] MOL2 format, chain EA [auth C] mmCIF format, chain AA [auth C] mmCIF format, chain BA [auth C] mmCIF format, chain CA [auth C] mmCIF format, chain D [auth A] mmCIF format, chain DA [auth C] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain FA [auth C] mmCIF format, chain G [auth A] mmCIF format, chain GA [auth C] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain N [auth B] 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 S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B] mmCIF format, chain Z [auth C] mmCIF format, chain EA [auth C]	AA [auth C] BA [auth C] CA [auth C] D [auth A] DA [auth C] AA [auth C], BA [auth C], CA [auth C], D [auth A], DA [auth C], E [auth A], EA [auth C], F [auth A], FA [auth C], G [auth A], GA [auth C], H [auth A], I [auth A], J [auth A], N [auth B], O [auth B], P [auth B], Q [auth B], R [auth B], S [auth B], T [auth B], U [auth B], V [auth B], Z [auth C]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain AA [auth C] Focus chain BA [auth C] Focus chain CA [auth C] Focus chain D [auth A] Focus chain DA [auth C] Focus chain E [auth A] Focus chain EA [auth C] Focus chain F [auth A] Focus chain FA [auth C] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain Z [auth C] Interactions & Density Focus chain AA [auth C] Focus chain BA [auth C] Focus chain CA [auth C] Focus chain D [auth A] Focus chain DA [auth C] Focus chain E [auth A] Focus chain EA [auth C] Focus chain F [auth A] Focus chain FA [auth C] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Focus chain Z [auth C]