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PDBsum entry 4tms
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Transferase (methyltransferase) PDB id
4tms

 

 

 

 

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Contents
Protein chain
316 a.a. *
Ligands
PO4
Waters ×39
* Residue conservation analysis
PDB id:
4tms
Name: Transferase (methyltransferase)
Title: Plastic adaptation toward mutations in proteins: structural comparison of thymidylate synthases
Structure: Thymidylate synthase. Chain: a. Engineered: yes
Source: Lactobacillus casei. Organism_taxid: 1582
Biol. unit: Dimer (from PQS)
Resolution:
2.35Å     R-factor:   0.193    
Authors: J.Finer-Moore,R.Stroud
Key ref: K.M.Perry et al. (1990). Plastic adaptation toward mutations in proteins: structural comparison of thymidylate synthases. Proteins, 8, 315-333. PubMed id: 2128651
Date:
07-Jan-92     Release date:   15-Jan-92    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00469  (TYSY_LACCA) -  Thymidylate synthase from Lacticaseibacillus casei
Seq:
Struc: 		316 a.a.
316 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.45  - thymidylate synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Folate Coenzymes
      Reaction: dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 7,8-dihydrofolate + dTMP
dUMP
 + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate
 = 7,8-dihydrofolate
 + dTMP
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Proteins 8:315-333 (1990)
PubMed id: 2128651  
 
 
Plastic adaptation toward mutations in proteins: structural comparison of thymidylate synthases.
K.M.Perry, E.B.Fauman, J.S.Finer-Moore, W.R.Montfort, G.F.Maley, F.Maley, R.M.Stroud.
 
  ABSTRACT  
 
The structure of thymidylate synthase (TS) from Escherichia coli was solved from cubic crystals with a = 133 A grown under reducing conditions at pH 7.0, and refined to R = 22% at 2.1 A resolution. The structure is compared with that from Lactobacillus casei solved to R = 21% at 2.3 A resolution. The structures are compared using a difference distance matrix, which identifies a common core of residues that retains the same relationship to one another in both species. After subtraction of the effects of a 50 amino acid insert present in Lactobacillus casei, differences in position of atoms correlate with temperature factors and with distance from the nearest substituted residue. The dependence of structural difference on thermal factor is parameterized and reflects both errors in coordinates that correlate with thermal factor, and the increased width of the energy well in which atoms of high thermal factor lie. The dependence of structural difference on distance from the nearest substitution also depends on thermal factors and shows an exponential dependence with half maximal effect at 3.0 A from the substitution. This represents the plastic accommodation of the protein which is parameterized in terms of thermal B factor and distance from a mutational change.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21318388 B.Luo, S.R.Johnson, L.Lebioda, and S.H.Berger (2011).
Evolution of metamorphism in thymidylate synthases within the primate lineages.
  J Mol Evol, 72, 306-314.  
20577818 M.Chanama, S.Chanama, P.J.Shaw, P.Chitnumsub, U.Leartsakulpanich, and Y.Yuthavong (2011).
Formation of catalytically active cross-species heterodimers of thymidylate synthase from Plasmodium falciparum and Plasmodium vivax.
  Mol Biol Rep, 38, 1029-1037.  
20714488 N.Kanaan, M.Roca, I.Tuñón, S.Martí, and V.Moliner (2010).
Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase.
  Phys Chem Chem Phys, 12, 11657-11664.  
21118569 Y.H.Ching, R.J.Munroe, J.L.Moran, A.K.Barker, E.Mauceli, T.Fennell, F.Dipalma, K.Lindblad-Toh, L.M.Abcunas, J.F.Gilmour, T.P.Harris, S.L.Kloet, Y.Luo, J.L.McElwee, W.Mu, H.K.Park, D.L.Rogal, K.J.Schimenti, L.Shen, M.Shindo, J.Y.Shou, E.K.Stenson, P.J.Stover, and J.C.Schimenti (2010).
High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5.
  BMC Genet, 11, 106.  
19298824 A.Alian, A.DeGiovanni, S.L.Griner, J.S.Finer-Moore, and R.M.Stroud (2009).
Crystal structure of an RluF-RNA complex: a base-pair rearrangement is the key to selectivity of RluF for U2604 of the ribosome.
  J Mol Biol, 388, 785-800.
PDB code: 3dh3
19569192 L.L.Lovelace, S.R.Johnson, L.M.Gibson, B.J.Bell, S.H.Berger, and L.Lebioda (2009).
Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation.
  Protein Sci, 18, 1628-1636.
PDB codes: 3egy 3ehi
18270995 S.Ferrari, V.Losasso, and M.P.Costi (2008).
Sequence-based identification of specific drug target regions in the thymidylate synthase enzyme family.
  ChemMedChem, 3, 392-401.  
18648921 Y.Wang, and X.Zhang (2008).
Identification and characterization of a novel thymidylate synthase from deep-sea thermophilic bacteriophage Geobacillus virus E2.
  Virus Genes, 37, 218-224.  
17320904 H.Pan, J.D.Ho, R.M.Stroud, and J.Finer-Moore (2007).
The crystal structure of E. coli rRNA pseudouridine synthase RluE.
  J Mol Biol, 367, 1459-1470.
PDB codes: 2olw 2oml
16615077 R.R.Sotelo-Mundo, L.Changchien, F.Maley, and W.R.Montfort (2006).
Crystal structures of thymidylate synthase mutant R166Q: structural basis for the nearly complete loss of catalytic activity.
  J Biochem Mol Toxicol, 20, 88-92.
PDB codes: 1ffl 1fwm
16204883 J.S.Finer-Moore, A.C.Anderson, R.H.O'Neil, M.P.Costi, S.Ferrari, J.Krucinski, and R.M.Stroud (2005).
The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.
  Acta Crystallogr D Biol Crystallogr, 61, 1320-1334.
PDB codes: 2a9w 2aaz
15766524 T.T.Lee, S.Agarwalla, and R.M.Stroud (2005).
A unique RNA Fold in the RumA-RNA-cofactor ternary complex contributes to substrate selectivity and enzymatic function.
  Cell, 120, 599-611.
PDB code: 2bh2
14700626 S.Ferrari, P.M.Costi, and R.C.Wade (2003).
Inhibitor specificity via protein dynamics: insights from the design of antibacterial agents targeted against thymidylate synthase.
  Chem Biol, 10, 1183-1193.  
11316879 R.Almog, C.A.Waddling, F.Maley, G.F.Maley, and P.Van Roey (2001).
Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP.
  Protein Sci, 10, 988-996.
PDB codes: 1hzw 1i00
11590022 T.A.Fritz, D.Tondi, J.S.Finer-Moore, M.P.Costi, and R.M.Stroud (2001).
Predicting and harnessing protein flexibility in the design of species-specific inhibitors of thymidylate synthase.
  Chem Biol, 8, 981-995.
PDB code: 1jg0
10944209 D.A.Erlanson, A.C.Braisted, D.R.Raphael, M.Randal, R.M.Stroud, E.M.Gordon, and J.A.Wells (2000).
Site-directed ligand discovery.
  Proc Natl Acad Sci U S A, 97, 9367-9372.
PDB codes: 1f4b 1f4c 1f4d 1f4e 1f4f 1f4g
10818348 T.R.Schneider (2000).
Objective comparison of protein structures: error-scaled difference distance matrices.
  Acta Crystallogr D Biol Crystallogr, 56, 714-721.  
10220346 D.J.Steadman, H.T.Spencer, R.B.Dunlap, and S.H.Berger (1999).
Substitution at residue 214 of human thymidylate synthase alters nucleotide binding and isomerization of ligand-protein complexes.
  Biochemistry, 38, 5582-5587.  
10097112 J.Ju, J.Pedersen-Lane, F.Maley, and E.Chu (1999).
Regulation of p53 expression by thymidylate synthase.
  Proc Natl Acad Sci U S A, 96, 3769-3774.  
10026292 S.Hazebrouck, F.Maley, V.Machtelinckx, P.Sonigo, and J.J.Kupiec (1999).
Structural and functional analysis of surface domains unique to bacteriophage T4 thymidylate synthase.
  Biochemistry, 38, 2094-2101.  
10024022 V.Prasanna, B.Gopal, M.R.Murthy, D.V.Santi, and P.Balaram (1999).
Effect of amino acid substitutions at the subunit interface on the stability and aggregation properties of a dimeric protein: role of Arg 178 and Arg 218 at the Dimer interface of thymidylate synthase.
  Proteins, 34, 356-368.  
9753479 C.R.Sage, M.D.Michelitsch, T.J.Stout, D.Biermann, R.Nissen, J.Finer-Moore, and R.M.Stroud (1998).
D221 in thymidylate synthase controls conformation change, and thereby opening of the imidazolidine.
  Biochemistry, 37, 13893-13901.
PDB codes: 1bjg 1dna
9585519 D.J.Steadman, P.S.Zhao, H.T.Spencer, R.B.Dunlap, and S.H.Berger (1998).
A structural role for glutamine 214 in human thymidylate synthase.
  Biochemistry, 37, 7089-7095.  
9748254 D.M.Landis, and L.A.Loeb (1998).
Random sequence mutagenesis and resistance to 5-fluorouridine in human thymidylate synthases.
  J Biol Chem, 273, 25809-25817.  
  9568900 D.M.Lorber, and B.K.Shoichet (1998).
Flexible ligand docking using conformational ensembles.
  Protein Sci, 7, 938-950.  
9436180 M.P.Costi (1998).
Thymidylate synthase inhibition: a structure-based rationale for drug design.
  Med Res Rev, 18, 21-42.  
9705308 N.C.Horton, and J.J.Perona (1998).
Recognition of flanking DNA sequences by EcoRV endonuclease involves alternative patterns of water-mediated contacts.
  J Biol Chem, 273, 21721-21729.
PDB code: 1bgb
9811827 N.C.Horton, K.J.Newberry, and J.J.Perona (1998).
Metal ion-mediated substrate-assisted catalysis in type II restriction endonucleases.
  Proc Natl Acad Sci U S A, 95, 13489-13494.
PDB code: 1bss
9485411 R.B.Rose, C.S.Craik, and R.M.Stroud (1998).
Domain flexibility in retroviral proteases: structural implications for drug resistant mutations.
  Biochemistry, 37, 2607-2621.
PDB code: 1az5
9687366 T.J.Stout, C.R.Sage, and R.M.Stroud (1998).
The additivity of substrate fragments in enzyme-ligand binding.
  Structure, 6, 839-848.
PDB codes: 1an5 1aob 1bdu 1bid 1ddu 1tdu 1tjs 1trg
9778348 T.J.Stout, U.Schellenberger, D.V.Santi, and R.M.Stroud (1998).
Crystal structures of a unique thermal-stable thymidylate synthase from Bacillus subtilis.
  Biochemistry, 37, 14736-14747.
PDB codes: 1bko 1bkp 1bsf 1bsp
9012674 M.R.Sawaya, and J.Kraut (1997).
Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence.
  Biochemistry, 36, 586-603.
PDB codes: 1dre 1ra1 1ra2 1ra3 1ra8 1ra9 1rb2 1rb3 1rc4 1rd7 1re7 1rf7 1rg7 1rh3 1rx1 1rx2 1rx3 1rx4 1rx5 1rx6 1rx7 1rx8 1rx9
  9416600 P.Strop, L.Changchien, F.Maley, and W.R.Montfort (1997).
Crystal structures of a marginally active thymidylate synthase mutant, Arg 126-->Glu.
  Protein Sci, 6, 2504-2511.
PDB codes: 1aiq 1ajm
  9003601 S.Latouche, E.Ortona, E.Mazars, P.Margutti, E.Tamburrini, A.Siracusano, K.Guyot, M.Nigou, and P.Roux (1997).
Biodiversity of Pneumocystis carinii hominis: typing with different DNA regions.
  J Clin Microbiol, 35, 383-387.  
9535167 W.R.Montfort, and A.Weichsel (1997).
Thymidylate synthase: structure, inhibition, and strained conformations during catalysis.
  Pharmacol Ther, 76, 29-43.  
8888067 B.L.Stoddard (1996).
Intermediate trapping and laue X-ray diffraction: potential for enzyme mechanism, dynamics, and inhibitor screening.
  Pharmacol Ther, 70, 215-256.  
8679643 C.H.Chen, R.A.Davis, and F.Maley (1996).
Thermodynamic stabilization of nucleotide binding to thymidylate synthase by a potent benzoquinazoline folate analogue inhibitor.
  Biochemistry, 35, 8786-8793.  
8973201 C.R.Sage, E.E.Rutenber, T.J.Stout, and R.M.Stroud (1996).
An essential role for water in an enzyme reaction mechanism: the crystal structure of the thymidylate synthase mutant E58Q.
  Biochemistry, 35, 16270-16281.
PDB codes: 1kce 1zpr
8939755 E.E.Rutenber, and R.M.Stroud (1996).
Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity.
  Structure, 4, 1317-1324.
PDB code: 2kce
8628226 I.M.Schlichtherle, D.S.Roos, and J.L.Van Houten (1996).
Cloning and molecular analysis of the bifunctional dihydrofolate reductase-thymidylate synthase gene in the ciliated protozoan Paramecium tetraurelia.
  Mol Gen Genet, 250, 665-673.  
8920005 P.Reche, R.Arrebola, D.V.Santi, D.Gonzalez-Pacanowska, and L.M.Ruiz-Perez (1996).
Expression and characterization of the Trypanosoma cruzi dihydrofolate reductase domain.
  Mol Biochem Parasitol, 76, 175-185.  
8805515 T.J.Stout, and R.M.Stroud (1996).
The complex of the anti-cancer therapeutic, BW1843U89, with thymidylate synthase at 2.0 A resolution: implications for a new mode of inhibition.
  Structure, 4, 67-77.
PDB code: 1syn
7708505 D.M.Voeller, L.M.Changchien, G.F.Maley, F.Maley, T.Takechi, R.E.Turner, W.R.Montfort, C.J.Allegra, and E.Chu (1995).
Characterization of a specific interaction between Escherichia coli thymidylate synthase and Escherichia coli thymidylate synthase mRNA.
  Nucleic Acids Res, 23, 869-875.  
7728138 E.Mazars, C.Odberg-Ferragut, E.Dei-Cas, M.N.Fourmaux, E.M.Aliouat, M.Brun-Pascaud, G.Mougeot, and D.Camus (1995).
Polymorphism of the thymidylate synthase gene of Pneumocystis carinii from different host species.
  J Eukaryot Microbiol, 42, 26-32.  
  8528087 H.L.Schubert, E.B.Fauman, J.A.Stuckey, J.E.Dixon, and M.A.Saper (1995).
A ligand-induced conformational change in the Yersinia protein tyrosine phosphatase.
  Protein Sci, 4, 1904-1913.
PDB code: 1yts
8749362 J.L.Smith (1995).
Enzymes of nucleotide synthesis.
  Curr Opin Struct Biol, 5, 752-757.  
9383465 J.T.Kealey, J.Eckstein, and D.V.Santi (1995).
Role of the conserved tryptophan 82 of Lactobacillus casei thymidylate synthase.
  Chem Biol, 2, 609-614.  
  8563637 R.M.Stroud, and E.B.Fauman (1995).
Significance of structural changes in proteins: expected errors in refined protein structures.
  Protein Sci, 4, 2392-2404.  
7972121 D.H.Bechhofer, K.K.Hue, and D.A.Shub (1994).
An intron in the thymidylate synthase gene of Bacillus bacteriophage beta 22: evidence for independent evolution of a gene, its group I intron, and the intron open reading frame.
  Proc Natl Acad Sci U S A, 91, 11669-11673.  
7812717 L.W.Hardy, D.F.Pacitti, and E.Nalivaika (1994).
Use of a purified heterodimer to test negative cooperativity as the basis of substrate inactivation of Escherichia coli thymidylate synthase (Asn177-->Asp).
  Structure, 2, 833-838.  
  7757001 N.V.Grishin, and M.A.Phillips (1994).
The subunit interfaces of oligomeric enzymes are conserved to a similar extent to the overall protein sequences.
  Protein Sci, 3, 2455-2458.  
  7920258 P.J.Greene, P.L.Yu, J.Zhao, C.A.Schiffer, and D.Santi (1994).
Expression, purification, and characterization of thymidylate synthase from Lactococcus lactis.
  Protein Sci, 3, 1114-1116.  
8378336 L.Liu, and D.V.Santi (1993).
Asparagine 229 in thymidylate synthase contributes to, but is not essential for, catalysis.
  Proc Natl Acad Sci U S A, 90, 8604-8608.  
8415683 P.Schimmell (1993).
Functional analysis suggests unexpected role for conserved active-site residue in enzyme of known structure.
  Proc Natl Acad Sci U S A, 90, 9235-9236.  
8265565 S.Daopin, M.Li, and D.R.Davies (1993).
Crystal structure of TGF-beta 2 refined at 1.8 A resolution.
  Proteins, 17, 176-192.  
1368433 C.Eigenbrot, and A.A.Kossiakoff (1992).
Structural consequences of mutation.
  Curr Opin Biotechnol, 3, 333-337.  
1557349 J.S.Finer-Moore, A.A.Kossiakoff, J.H.Hurley, T.Earnest, and R.M.Stroud (1992).
Solvent structure in crystals of trypsin determined by X-ray and neutron diffraction.
  Proteins, 12, 203-222.
PDB code: 5ptp
  1304920 K.M.Perry, M.Pookanjanatavip, J.Zhao, D.V.Santi, and R.M.Stroud (1992).
Reversible dissociation and unfolding of the dimeric protein thymidylate synthase.
  Protein Sci, 1, 796-800.  
1409689 L.W.Hardy, and E.Nalivaika (1992).
Asn177 in Escherichia coli thymidylate synthase is a major determinant of pyrimidine specificity.
  Proc Natl Acad Sci U S A, 89, 9725-9729.  
1881877 T.Earnest, E.Fauman, C.S.Craik, and R.Stroud (1991).
1.59 A structure of trypsin at 120 K: comparison of low temperature and room temperature structures.
  Proteins, 10, 171-187.
PDB code: 1dpo
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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