5HM3

2.25 Angstrom Resolution Crystal Structure of Long-chain-fatty-acid-AMP Ligase FadD32 from Mycobacterium tuberculosis in complex with Inhibitor 5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.188 

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This is version 1.1 of the entry. See complete history


Literature

Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis.

Kuhn, M.L.Alexander, E.Minasov, G.Page, H.J.Warwrzak, Z.Shuvalova, L.Flores, K.J.Wilson, D.J.Shi, C.Aldrich, C.C.Anderson, W.F.

(2016) ACS Infect Dis 2: 579-591

  • DOI: https://doi.org/10.1021/acsinfecdis.6b00082
  • Primary Citation of Related Structures:  
    5HM3

  • PubMed Abstract: 

    Mycolic acids are indispensible lipids of Mycobacterium tuberculosis ( Mtb ), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure of Mtb FadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.


  • Organizational Affiliation

    Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States; Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Long-chain-fatty-acid--AMP ligase FadD32657Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: fadD32Rv3801c
EC: 6.2.1
UniProt
Find proteins for O53580 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore O53580 
Go to UniProtKB:  O53580
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO53580
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
649
Query on 649

Download Ideal Coordinates CCD File 
B [auth A]5'-O-[(11-phenoxyundecanoyl)sulfamoyl]adenosine
C27 H38 N6 O8 S
VLRIGNDIFPKPGQ-ZCIWVVNKSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
H [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
MSE
Query on MSE
A
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Binding Affinity Annotations 
IDSourceBinding Affinity
649 Binding MOAD:  5HM3 IC50: 6800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.779α = 90
b = 74.558β = 90
c = 127.762γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-03
    Type: Initial release
  • Version 1.1: 2016-09-07
    Changes: Database references