Crystal structure of the secreted form of antigen 85C reveals potential targets for mycobacterial drugs and vaccines.
The antigen 85 (ag85) complex, composed of three proteins (ag85A, B and C), is a major protein component of the Mycobacterium tuberculosis cell wall. Each protein possesses a mycolyltransferase activity required for the biogenesis of trehalose dimycolate (cord factor), a dominant structure necessary for maintaining cell wall integrity. The crystal structure of recombinant ag85C from M. tuberculosis, refined to a resolution of 1.5 A, reveals an alpha/beta-hydrolase polypeptide fold, and a catalytic triad formed by Ser 124, Glu 228 and His 260. ag85C complexed with a covalent inhibitor implicates residues Leu 40 and Met 125 as components of the oxyanion hole. A hydrophobic pocket and tunnel extending 21 A into the core of the protein indicates the location of a probable trehalose monomycolate binding site. Also, a large region of conserved surface residues among ag85A, B and C is a probable site for the interaction of ag85 proteins with human fibronectin.
Ronning
D R
DR
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77844-2128, USA.
Klabunde
T
T
Besra
G S
GS
Vissa
V D
VD
Belisle
J T
JT
Sacchettini
J C
JC
D000217:Acyltransferases; D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000995:Antitubercular Agents / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D002473:Cell Wall / Q000378:metabolism; D003311:Cord Factors / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D003311:Cord Factors; D005353:Fibronectins; D010755:Organophosphates; D011994:Recombinant Proteins; C034789:diethyl phosphate; D000217:Acyltransferases; C119774:antigen 85C, Mycobacterium tuberculosis