Linked Life Data

9371085

Source:http://linkedlifedata.com/resource/pubmed/id/9371085

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1997-12-23
pubmed:abstractText
Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target for the control of parasitic infections. The enzyme catalyzes the NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed step in guanosine monophosphate (GMP) biosynthesis. We have determined the crystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the apo form at 2.3 A resolution and the enzyme-XMP complex at 2.6 A resolution. The enzyme forms a cyclic (C4) homotetramer. The core domain of each monomer forms an eight-stranded parallel beta/alpha barrel with the enzyme active site at the C-termini of the barrel beta strands which lies near the center of the fourfold axis of the tetramer. While the electron-density for XMP in the complex structure is well-defined, the NAD cofactor and a nearby loop containing the catalytic cysteine (Cys-319) are disordered. This disorder at the active site suggests that a high degree of flexibility may be inherent to the catalytic function of IMPDH, making this area a difficult target for structure-based inhibitor design. Unlike IMPDHs from other species, the T. foetus enzyme coordinates the substrate phosphate with a single arginine guanidinium in the active site. Furthermore, a deep groove extends 8 A from the substrate phosphate away from the sugar. This structural uniqueness forms the basis of our efforts to design compounds that specifically inhibit the parasite enzyme.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0014-4894
pubmed:author
pubmed:issnType
Print
pubmed:volume
87
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
203-11
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Tritrichomonas foetus: a strategy for structure-based inhibitor design of a protozoan inosine-5'-monophosphate dehydrogenase.
pubmed:affiliation
Department of Molecular Biology and Biochemistry, University of California, Irvine 92697, USA. hudel@uci.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't