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3fs6

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Revision as of 10:32, 9 September 2020

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

Structural highlights

3fs6 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1u72
Activity:	Dihydrofolate reductase, with EC number 1.5.1.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM: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.^[1] ^[2]

Function

[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.^[3] ^[4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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 (dagger) (double dagger).,Cody V, Pace J, Makin J, Piraino J, Queener SF, Rosowsky A Biochemistry. 2009 Feb 5. PMID:19196009^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
↑ Cody V, Pace J, Makin J, Piraino J, Queener SF, Rosowsky A. Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes (dagger) (double dagger). Biochemistry. 2009 Feb 5. PMID:19196009 doi:10.1021/bi801960h

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Correlations of Inhibitor Kinetics for Pneumocystis jirovecii and Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes==
-<StructureSection load='3fs6' size='340' side='right' caption='[[3fs6]], [[Resolution|resolution]] 1.23&Aring;' scene=''>
+<StructureSection load='3fs6' size='340' side='right'caption='[[3fs6]], [[Resolution|resolution]] 1.23&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3fs6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FS6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3fs6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://proteopedia.org/fgij/fg.htm?mol=3FS6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>
+</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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1u72|1u72]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fs6 OCA], [http://pdbe.org/3fs6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fs6 RCSB], [http://www.ebi.ac.uk/pdbsum/3fs6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fs6 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3fs6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fs6 OCA], [http://pdbe.org/3fs6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fs6 RCSB], [http://www.ebi.ac.uk/pdbsum/3fs6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fs6 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 34: / Line 34: @@
 ==See Also==
-*[[Dihydrofolate reductase|Dihydrofolate reductase]]
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
 == References ==
 <references/>
@@ Line 41: / Line 41: @@
 [[Category: Dihydrofolate reductase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Cody, V]]
 [[Category: Makin, J]]

3fs6

From Proteopedia

Revision as of 10:32, 9 September 2020

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

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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