1pdb: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1pdb.gif|left|200px]]<br />
-<applet load="1pdb" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1pdb, resolution 2.2&Aring;" />
-'''Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase'''<br />
-==Overview==
+==Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase==
-Structural data are reported for the first example of the potent, antifolate inhibitor, 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxy-N-methylanilino)methyl]pyrido, [2,3-d]pyrimidine (1) in complex with human dihydrofolate reductase, (hDHFR) and NADPH. Small differences in crystallization conditions, resulted in the growth of two different forms of a binary complex. The, structure determination of an additional crystal of a ternary complex of, hDHFR with NADPH and (1) grown under similar conditions is also reported., Diffraction data were collected to 2.1 A resolution for an R3 lattice from, a hDHFR ternary complex with NADPH and (1) and to 2.2 A resolution from a, binary complex. Data were also collected to 2.1 A resolution from a binary, complex with hDHFR and (1) in the first example of a tetragonal P4(3)2(1)2, lattice. Comparison of the intermolecular contacts among these structures, reveals differences in the backbone conformation (1.9-3.2 A) for flexible, loop regions (residues 40-46, 77-83 and 103-107) that reflect differences, in the packing environment between the rhombohedral and tetragonal space, groups. Analysis of the packing environments shows that the tetragonal, lattice is more tightly packed, as reflected in its smaller V(M) value and, lower solvent content. The conformation of the inhibitor (1) is similar in, all structures and is also similar to that observed for TMQ, the parent, quinazoline compound. The activity profile for this series of 5-deaza, N-substituted non-classical trimethoxybenzyl antifolates shows that the, N10-CH(3) substituted (1) has the greatest potency and selectivity for, Toxoplasma gondii DHFR (tgDHFR) compared with its N-H or N-CHO analogs., Models of the tgDHFR active site indicate preferential contacts with (1), that are not present in either the human or Pneumocystis carinii DHFR, structures. Differences in the acidic residue (Glu30 versus Asp for, tgDHFR) affect the precise positioning of the diaminopyridopyrimidine, ring, while changes in other residues, particularly at positions 60 and 64, (Leu versus Met and Asn versus Phe), involve interactions with the, trimethoxybenzyl substituents.
+<StructureSection load='1pdb' size='340' side='right'caption='[[1pdb]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1pdb]] 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=1PDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PDB FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pdb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pdb OCA], [https://pdbe.org/1pdb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pdb RCSB], [https://www.ebi.ac.uk/pdbsum/1pdb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pdb 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/pd/1pdb_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=1pdb ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Structural data are reported for the first example of the potent antifolate inhibitor 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxy-N-methylanilino)methyl]pyrido [2,3-d]pyrimidine (1) in complex with human dihydrofolate reductase (hDHFR) and NADPH. Small differences in crystallization conditions resulted in the growth of two different forms of a binary complex. The structure determination of an additional crystal of a ternary complex of hDHFR with NADPH and (1) grown under similar conditions is also reported. Diffraction data were collected to 2.1 A resolution for an R3 lattice from a hDHFR ternary complex with NADPH and (1) and to 2.2 A resolution from a binary complex. Data were also collected to 2.1 A resolution from a binary complex with hDHFR and (1) in the first example of a tetragonal P4(3)2(1)2 lattice. Comparison of the intermolecular contacts among these structures reveals differences in the backbone conformation (1.9-3.2 A) for flexible loop regions (residues 40-46, 77-83 and 103-107) that reflect differences in the packing environment between the rhombohedral and tetragonal space groups. Analysis of the packing environments shows that the tetragonal lattice is more tightly packed, as reflected in its smaller V(M) value and lower solvent content. The conformation of the inhibitor (1) is similar in all structures and is also similar to that observed for TMQ, the parent quinazoline compound. The activity profile for this series of 5-deaza N-substituted non-classical trimethoxybenzyl antifolates shows that the N10-CH(3) substituted (1) has the greatest potency and selectivity for Toxoplasma gondii DHFR (tgDHFR) compared with its N-H or N-CHO analogs. Models of the tgDHFR active site indicate preferential contacts with (1) that are not present in either the human or Pneumocystis carinii DHFR structures. Differences in the acidic residue (Glu30 versus Asp for tgDHFR) affect the precise positioning of the diaminopyridopyrimidine ring, while changes in other residues, particularly at positions 60 and 64 (Leu versus Met and Asn versus Phe), involve interactions with the trimethoxybenzyl substituents.
-==Disease==
+Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase.,Cody V, Luft JR, Pangborn W, Gangjee A Acta Crystallogr D Biol Crystallogr. 2003 Sep;59(Pt 9):1603-9. Epub 2003, Aug 19. PMID:12925791<ref>PMID:12925791</ref>
-Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126060 126060]]
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-PDB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1PDB OCA].
+</div>
+<div class="pdbe-citations 1pdb" style="background-color:#fffaf0;"></div>
-==Reference==
+==See Also==
-Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase., Cody V, Luft JR, Pangborn W, Gangjee A, Acta Crystallogr D Biol Crystallogr. 2003 Sep;59(Pt 9):1603-9. Epub 2003, Aug 19. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12925791 12925791]
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
-[[Category: Dihydrofolate reductase]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Cody, V.]]
+[[Category: Cody V]]
-[[Category: Gangjee, A.]]
+[[Category: Gangjee A]]
-[[Category: Luft, J.R.]]
+[[Category: Luft JR]]
-[[Category: Pangborn, W.]]
+[[Category: Pangborn W]]
-[[Category: human dihydrofolate reductase inhibitor complexes]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:42:21 2007''