1dg7

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:1dg7.gif|left|200px]]
+
{{Seed}}
 +
[[Image:1dg7.png|left|200px]]
<!--
<!--
Line 9: Line 10:
{{STRUCTURE_1dg7| PDB=1dg7 | SCENE= }}
{{STRUCTURE_1dg7| PDB=1dg7 | SCENE= }}
-
'''DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210'''
+
===DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210===
-
==Overview==
+
<!--
-
Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate and is essential for the synthesis of thymidylate, purines and several amino acids. Inhibition of the enzyme's activity leads to arrest of DNA synthesis and cell death. The enzyme has been studied extensively as a drug target for bacterial, protozoal and fungal infections, and also for neoplastic and autoimmune diseases. Here, we report the crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis, a human pathogen responsible for the death of millions of human beings per year. Three crystal structures of ternary complexes of M. tuberculosis DHFR with NADP and different inhibitors have been determined, as well as the binary complex with NADP, with resolutions ranging from 1.7 to 2.0 A. The three DHFR inhibitors are the anticancer drug methotrexate, the antimicrobial trimethoprim and Br-WR99210, an analogue of the antimalarial agent WR99210. Structural comparison of these complexes with human dihydrofolate reductase indicates that the overall protein folds are similar, despite only 26 % sequence identity, but that the environments of both NADP and of the inhibitors contain interesting differences between the enzymes from host and pathogen. Specifically, residues Ala101 and Leu102 near the N6 of NADP are distinctly more hydrophobic in the M. tuberculosis than in the human enzyme. Another striking difference occurs in a region near atoms N1 and N8 of methotrexate, which is also near atom N1 of trimethoprim, and near the N1 and two methyl groups of Br-WR99210. A glycerol molecule binds here in a pocket of the M. tuberculosis DHFR:MTX complex, while this pocket is essentially filled with hydrophobic side-chains in the human enzyme. These differences between the enzymes from pathogen and host provide opportunities for designing new selective inhibitors of M. tuberculosis DHFR.
+
The line below this paragraph, {{ABSTRACT_PUBMED_10623528}}, adds the Publication Abstract to the page
 +
(as it appears on PubMed at http://www.pubmed.gov), where 10623528 is the PubMed ID number.
 +
-->
 +
{{ABSTRACT_PUBMED_10623528}}
==About this Structure==
==About this Structure==
Line 39: Line 43:
[[Category: Tuberculosis]]
[[Category: Tuberculosis]]
[[Category: Wr99210]]
[[Category: Wr99210]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:49:24 2008''
+
 
 +
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 23:02:03 2008''

Revision as of 20:02, 30 June 2008

Image:1dg7.png

Template:STRUCTURE 1dg7

DIHYDROFOLATE REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS COMPLEXED WITH NADPH AND 4-BROMO WR99210

Template:ABSTRACT PUBMED 10623528

About this Structure

1DG7 is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.

Reference

Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs., Li R, Sirawaraporn R, Chitnumsub P, Sirawaraporn W, Wooden J, Athappilly F, Turley S, Hol WG, J Mol Biol. 2000 Jan 14;295(2):307-23. PMID:10623528

Page seeded by OCA on Mon Jun 30 23:02:03 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1dg7"
Personal tools