2fzh: Difference between revisions

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[[Image:2fzh.jpg|left|200px]]
{{Seed}}
[[Image:2fzh.png|left|200px]]


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{{STRUCTURE_2fzh|  PDB=2fzh  |  SCENE=  }}  
{{STRUCTURE_2fzh|  PDB=2fzh  |  SCENE=  }}  


'''New Insights into Dihydrofolate Reductase Interactions: Analysis of Pneumocystis carinii and Mouse DHFR Complexes with NADPH and Two Highly Potent Trimethoprim Derivatives'''
===New Insights into Dihydrofolate Reductase Interactions: Analysis of Pneumocystis carinii and Mouse DHFR Complexes with NADPH and Two Highly Potent Trimethoprim Derivatives===




==Overview==
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Structural data are reported for two highly potent antifolates, 2,4-diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (PY1011), with 5000-fold selectivity for Pneumocystis carinii dihydrofolate reductase (pcDHFR), relative to rat liver DHFR, and 2,4-diamino-5-[2-methoxy-5-(4-carboxybutyloxy)benzyl]pyrimidine (PY957), that has 80-fold selectivity for pcDHFR. Crystal structures are reported for NADPH ternary complexes with PY957 and pcDHFR, refined to 2.2 A resolution; with PY1011 and pcDHFR, refined to 2.0 A resolution; and with PY1011 and mouse DHFR (mDHFR), refined to 2.2 A resolution. These results reveal that the carboxylate of the omega-carboxyalkyloxy side chain of these inhibitors form ionic interactions with the conserved Arg in the substrate binding pocket of DHFR. These data suggest that the enhanced inhibitory activity of PY1011 compared with PY957 is, in part, due to the favorable contacts with Phe69 of pcDHFR by the methylene carbons of the inhibitor side chain that are oriented by the triple bond of the 1-pentynyl side chain. These contacts are not present in the PY957 pcDHFR complex, or in the PY1011 mDHFR complex. In the structure of mDHFR the site of Phe69 in pcDHFR is occupied by Asn64. These data also revealed a preference for an unusual parallel ring stacking interaction between Tyr35 of the active site helix and Phe199 of the C-terminal beta sheet in pcDHFR and by Tyr33 and Phe179 in mDHFR that is independent of bound ligand. A unique His174-His187 parallel ring stacking interaction was also observed only in the structure of pcDHFR. These ring stacking interactions are rarely found in any other protein families and may serve to enhance protein stability.
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{{ABSTRACT_PUBMED_17019704}}


==About this Structure==
==About this Structure==
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[[Category: Ring stacking interaction]]
[[Category: Ring stacking interaction]]
[[Category: Trimethoprim derivative]]
[[Category: Trimethoprim derivative]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 04:30:12 2008''
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 16:29:47 2008''

Revision as of 13:29, 27 July 2008

File:2fzh.png

Template:STRUCTURE 2fzh

New Insights into Dihydrofolate Reductase Interactions: Analysis of Pneumocystis carinii and Mouse DHFR Complexes with NADPH and Two Highly Potent Trimethoprim Derivatives

Template:ABSTRACT PUBMED 17019704

About this Structure

2FZH is a Single protein structure of sequence from Pneumocystis carinii. Full crystallographic information is available from OCA.

Reference

New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent 5-(omega-carboxy(alkyloxy) trimethoprim derivatives reveals conformational correlations with activity and novel parallel ring stacking interactions., Cody V, Pace J, Chisum K, Rosowsky A, Proteins. 2006 Dec 1;65(4):959-69. PMID:17019704

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