PDBsum entry 6dft

Transferase

PDB id: 6dft

Contents

Protein chains

384 a.a.

(+ 0 more) 318 a.a.

364 a.a.

Ligands

NAD ×12

Metals

_NA

PDB id:

6dft

Name:

Transferase

Title:

Trypanosoma brucei deoxyhypusine synthase

Structure:

Deoxyhypusine synthase. Chain: a, c, e, g, i, k. Fragment: catalytic monomer. Engineered: yes. Deoxyhypusine synthase regulatory subunit. Chain: b, d, f, h, j, l. Fragment: pseudoenzyme monomer. Synonym: inactive deoxyhypusine synthase. Engineered: yes

Source:

Trypanosoma brucei. Organism_taxid: 5691. Gene: dhsc. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: dhsp.

Resolution:

3.50Å R-factor: 0.224 R-free: 0.262

Authors:

D.R.Tomchick,M.A.Phillips,G.A.Afanador

Key ref:

G.A.Afanador et al. (2018). Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs. Structure, 26, 1499. PubMed id: 30197036 DOI: 10.1016/j.str.2018.07.012

Date:

15-May-18 Release date: 08-Aug-18

Protein chains

Q38BX0  (DHYSC_TRYB2) -  Deoxyhypusine synthase from Trypanosoma brucei brucei (strain 927/4 GUTat10.1)

Seq: 461 a.a.

Struc: 384 a.a.

Protein chains

Q4GZD1  (DHYSP_TRYB2) -  Deoxyhypusine synthase regulatory subunit from Trypanosoma brucei brucei (strain 927/4 GUTat10.1)

Seq: 342 a.a.

Struc: 318 a.a.

Protein chain

Q38BX0  (DHYSC_TRYB2) -  Deoxyhypusine synthase from Trypanosoma brucei brucei (strain 927/4 GUTat10.1)

Seq: 461 a.a.

Struc: 364 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L: E.C.2.5.1.46 - deoxyhypusine synthase.
• Pathway: EC 2.5.1.46
• Reaction: [eIF5A protein]-L-lysine + spermidine = [eIF5A protein]-deoxyhypusine + propane-1,3-diamine
• Cofactor: NAD(+)

NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.str.2018.07.012

Structure 26:1499 (2018)

PubMed id: 30197036

Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.

G.A.Afanador, D.R.Tomchick, M.A.Phillips.

ABSTRACT

Trypanosoma brucei is a neglected tropical disease endemic to Africa. The polyamine spermidine is essential for post-translational hypusine modification of eukaryotic initiation factor 5A (eIF5A), which is catalyzed by deoxyhypusine synthase (TbDHS). In trypanosomatids, deoxyhypusine synthase (DHS) activity is dependent on heterotetramer formation between two paralogs, DHSc and DHSp, both with minimal activity on their own due to missing catalytic residues. We determined the X-ray structure of TbDHS showing a single functional shared active site is formed at the DHSc/DHSp heterodimer interface, with deficiencies in one subunit complemented by the other. Each heterodimer contains two NAD⁺ binding sites, one housed in the functional catalytic site and the second bound in a remnant dead site that lacks key catalytic residues. Functional analysis of these sites by site-directed mutagenesis identified long-range contributions to the catalytic site from the dead site. Differences between trypanosomatid and human DHS that could be exploited for drug discovery were identified.