PDBsum entry 4bge

Oxidoreductase

PDB id

4bge

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Contents

			Protein chains

					267 a.a.


					254 a.a.

			Ligands

					PYW ×6

			Waters ×727

PDB id:

4bge

Links

Name:

Oxidoreductase

Title:

Crystal structure of inha(s94a) mutant in complex with pyridomycin

Structure:

Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a, b, c, d, e, f. Synonym: enoyl-acp reductase,fas-ii enoyl-acp reductase,nadh- dependent 2-trans-enoyl-acp reductase. Engineered: yes. Mutation: yes

Source:

Mycobacterium tuberculosis (strain atcc 25618 / h37rv). Organism_taxid: 83332. Gene: inha, rv1484, mtcy277.05. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.25Å

R-factor:

0.242

R-free:

0.278

Authors:

F.Pojer,R.C.Hartkoorn,S.T.Cole

Key ref:

R.C.Hartkoorn et al. (2014). Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA. Nat Chem Biol, 10, 96-98. PubMed id: 24292073 DOI: 10.1038/nchembio.1405

Date:

26-Mar-13

Release date:

04-Dec-13

PROCHECK

	Headers

	References

Protein chains

P9WGR1 (INHA_MYCTU) - Enoyl-[acyl-carrier-protein] reductase [NADH] from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: Struc:					269 a.a. 267 a.a.*

Protein chains

P9WGR1 (INHA_MYCTU) - Enoyl-[acyl-carrier-protein] reductase [NADH] from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: Struc:					269 a.a. 254 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 2 residue positions (black crosses)



		Enzyme reactions

Enzyme class:

Chains A, B, C, D, E, F: E.C.1.3.1.9 - enoyl-[acyl-carrier-protein] reductase (NADH).

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

a 2,3-saturated acyl-[ACP] + NAD⁺ = a (2E)-enoyl-[ACP] + NADH + H⁺

2,3-saturated acyl-[ACP]	+	NAD(+)	=	(2E)-enoyl-[ACP]	+	NADH	+	H(+)

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

Added reference

DOI no: 10.1038/nchembio.1405	Nat Chem Biol 10:96-98 (2014)
PubMed id: 24292073

Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.
R.C.Hartkoorn, F.Pojer, J.A.Read, H.Gingell, J.Neres, O.P.Horlacher, K.H.Altmann, S.T.Cole.

ABSTRACT

Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.