3fs6

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (06:50, 6 September 2023) (edit) (undo)
 
(11 intermediate revisions not shown.)
Line 1: Line 1:
-
{{Seed}}
 
-
[[Image:3fs6.jpg|left|200px]]
 
-
<!--
+
==Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes==
-
The line below this paragraph, containing "STRUCTURE_3fs6", creates the "Structure Box" on the page.
+
<StructureSection load='3fs6' size='340' side='right'caption='[[3fs6]], [[Resolution|resolution]] 1.23&Aring;' scene=''>
-
You may change the PDB parameter (which sets the PDB file loaded into the applet)
+
== Structural highlights ==
-
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+
<table><tr><td colspan='2'>[[3fs6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FS6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FS6 FirstGlance]. <br>
-
or leave the SCENE parameter empty for the default display.
+
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.23&#8491;</td></tr>
-
-->
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DH1:2,4-DIAMINO-5-[2-METHOXY-5-(4-CARBOXYBUTYLOXY)BENZYL]PYRIMIDINE'>DH1</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
-
{{STRUCTURE_3fs6| PDB=3fs6 | SCENE= }}
+
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fs6 OCA], [https://pdbe.org/3fs6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fs6 RCSB], [https://www.ebi.ac.uk/pdbsum/3fs6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fs6 ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
 +
== Evolutionary Conservation ==
 +
[[Image:Consurf_key_small.gif|200px|right]]
 +
Check<jmol>
 +
<jmolCheckbox>
 +
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fs/3fs6_consurf.spt"</scriptWhenChecked>
 +
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
 +
<text>to colour the structure by Evolutionary Conservation</text>
 +
</jmolCheckbox>
 +
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3fs6 ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
To understand the role of specific active site residues in conferring selective dihydrofolate reductase (DHFR) inhibition from pathogenic organisms such as Pneumocystis carinii (pc) or Pneumocystis jirovecii (pj), the causative agent in AIDS pneumonia, it is necessary to evaluate the role of these residues in the human enzyme. We report the first kinetic parameters for DHFR from pjDHFR and pcDHFR with methotrexate (MTX), trimethoprim (TMP), and its potent analogue, PY957. We also report the mutagenesis and kinetic analysis of active site mutant proteins at positions 35 and 64 of human (h) DHFR and the crystal structure determinations of hDHFR ternary complexes of NADPH and PY957 with the wild-type DHFR enzyme, the single mutant protein, Gln35Lys, and two double mutant proteins, Gln35Ser/Asn64Ser and Gln35Ser/Asn64Phe. These substitutions place into human DHFR amino acids found at those sites in the opportunistic pathogens pcDHFR (Q35K/N64F) and pjDHFR (Q35S/N64S). The K(i) inhibition constant for PY957 showed greatest potency of the compound for the N64F single mutant protein (5.2 nM), followed by wild-type pcDHFR (K(i) 22 nM) and then wild-type hDHFR enzyme (K(i) 230 nM). Structural data reveal significant conformational changes in the binding interactions of PY957 in the hDHFR Q35S/N64F mutant protein complex compared to the other hDHFR mutant protein complexes and the pcDHFR ternary complex. The conformation of PY957 in the wild-type DHFR is similar to that observed for the single mutant protein. These data support the hypothesis that the enhanced selectivity of PY957 for pcDHFR is in part due to the contributions at positions 37 and 69 (pcDHFR numbering). This insight will help in the design of more selective inhibitors that target these opportunistic pathogens.
-
===Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes===
+
Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes (dagger) (double dagger).,Cody V, Pace J, Makin J, Piraino J, Queener SF, Rosowsky A Biochemistry. 2009 Feb 5. PMID:19196009<ref>PMID:19196009</ref>
 +
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 3fs6" style="background-color:#fffaf0;"></div>
-
<!--
+
==See Also==
-
The line below this paragraph, {{ABSTRACT_PUBMED_19196009}}, adds the Publication Abstract to the page
+
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
-
(as it appears on PubMed at http://www.pubmed.gov), where 19196009 is the PubMed ID number.
+
== References ==
-
-->
+
<references/>
-
{{ABSTRACT_PUBMED_19196009}}
+
__TOC__
-
 
+
</StructureSection>
-
==About this Structure==
+
-
3FS6 is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FS6 OCA].
+
-
 
+
-
==Reference==
+
-
<ref group="xtra">PMID:19196009</ref><references group="xtra"/>
+
-
[[Category: Dihydrofolate reductase]]
+
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Cody, V.]]
+
[[Category: Large Structures]]
-
[[Category: Makin, J.]]
+
[[Category: Cody V]]
-
[[Category: Pace, J.]]
+
[[Category: Makin J]]
-
[[Category: Piraino, J.]]
+
[[Category: Pace J]]
-
[[Category: Queener, S F.]]
+
[[Category: Piraino J]]
-
[[Category: Rosowsky, A.]]
+
[[Category: Queener SF]]
-
[[Category: Human wild type dhfr active site inhibitor]]
+
[[Category: Rosowsky A]]
-
[[Category: Nadp]]
+
-
[[Category: One-carbon metabolism]]
+
-
[[Category: Oxidoreductase]]
+
-
 
+
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Aug 19 13:12:10 2009''
+

Current revision

Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes

PDB ID 3fs6

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3fs6"
Personal tools