PDBsum entry 6tim

Isomerase(intramolecular oxidoreductase)

PDB id

6tim

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Contents

			Protein chains

					249 a.a. *

			Ligands

					G3P

			Waters ×91

* Residue conservation analysis

PDB id:

6tim

Links

Name:

Isomerase(intramolecular oxidoreductase)

Title:

The adaptability of the active site of trypanosomal triosephosphate isomerase as observed in the crystal structures of three different complexes

Structure:

Triosephosphate isomerase. Chain: a, b. Engineered: yes

Source:

Trypanosoma brucei brucei. Organism_taxid: 5702. Strain: brucei

Biol. unit:

Dimer (from PQS)

Resolution:

2.20Å

R-factor:

0.370

Authors:

M.E.M.Noble,R.K.Wierenga,W.G.J.Hol

Key ref:

M.E.Noble et al. (1991). The adaptability of the active site of trypanosomal triosephosphate isomerase as observed in the crystal structures of three different complexes. Proteins, 10, 50-69. PubMed id: 2062828

Date:

23-Apr-91

Release date:

15-Oct-92

PROCHECK

	Headers

	References

Protein chains

P04789 (TPIS_TRYBB) - Triosephosphate isomerase, glycosomal from Trypanosoma brucei brucei

Seq: Struc:					250 a.a. 249 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.5.3.1.1 - triose-phosphate isomerase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

D-glyceraldehyde 3-phosphate = dihydroxyacetone phosphate

D-glyceraldehyde 3-phosphate
Bound ligand (Het Group name = G3P)
corresponds exactly

dihydroxyacetone phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

	Proteins 10:50-69 (1991)
PubMed id: 2062828

The adaptability of the active site of trypanosomal triosephosphate isomerase as observed in the crystal structures of three different complexes.
M.E.Noble, R.K.Wierenga, A.M.Lambeir, F.R.Opperdoes, A.M.Thunnissen, K.H.Kalk, H.Groendijk, W.G.Hol.

ABSTRACT

Crystals of triosephosphate isomerase from Trypanosoma brucei brucei have been used in binding studies with three competitive inhibitors of the enzyme's activity. Highly refined structures have been deduced for the complexes between trypanosomal triosephosphate isomerase and a substrate analogue (glycerol-3-phosphate to 2.2 A), a transition state analogue (3-phosphonopropionic acid to 2.6 A), and a compound structurally related to both (3-phosphoglycerate to 2.2 A). The active site structures of these complexes were compared with each other, and with two previously determined structures of triosephosphate isomerase either free from inhibitor or complexed with sulfate. The comparison reveals three conformations available to the "flexible loop" near the active site of triosephosphate isomerase: open (no ligand), almost closed (sulfate), and fully closed (phosphate/phosphonate complexes). Also seen to be sensitive to the nature of the active site ligand is the catalytic residue Glu-167. The side chain of this residue occupies one of two discrete conformations in each of the structures so far observed. A "swung out" conformation unsuitable for catalysis is observed when sulfate, 3-phosphoglycerate, or no ligand is bound, while a "swung in" conformation ideal for catalysis is observed in the complexes with glycerol-3-phosphate or 3-phosphonopropionate. The water structure of the active site is different in all five structures. The results are discussed with respect to the triosephosphate isomerase structure function relationship, and with respect to an on-going drug design project aimed at the selective inhibition of glycolytic enzymes of T. brucei.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20919991

X.Zhang, Y.B.Teng, J.P.Liu, Y.X.He, K.Zhou, Y.Chen, and C.Z.Zhou (2010).
Structural insights into the catalytic mechanism of the yeast pyridoxal 5-phosphate synthase Snz1.

Biochem J, 432, 445-450.

PDB codes:

3o05 3o06 3o07

19089986

S.Donnini, A.Villa, G.Groenhof, A.E.Mark, R.K.Wierenga, and A.H.Juffer (2009).
Inclusion of ionization states of ligands in affinity calculations.

Proteins, 76, 138-150.

17646926

K.H.Kim (2007).
Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?

J Comput Aided Mol Des, 21, 421-435.

17444661

T.L.Amyes, and J.P.Richard (2007).
Enzymatic catalysis of proton transfer at carbon: activation of triosephosphate isomerase by phosphite dianion.

Biochemistry, 46, 5841-5854.

15911615

J.Zhu, J.W.Burgner, E.Harms, B.R.Belitsky, and J.L.Smith (2005).
A new arrangement of (beta/alpha)8 barrels in the synthase subunit of PLP synthase.

J Biol Chem, 280, 27914-27923.

PDB code:

1znn

16159918

L.C.Martin, G.B.Gloor, S.D.Dunn, and L.M.Wahl (2005).
Using information theory to search for co-evolving residues in proteins.

Bioinformatics, 21, 4116-4124.

12509510

G.Jogl, S.Rozovsky, A.E.McDermott, and L.Tong (2003).
Optimal alignment for enzymatic proton transfer: structure of the Michaelis complex of triosephosphate isomerase at 1.2-A resolution.

Proc Natl Acad Sci U S A, 100, 50-55.

PDB codes:

1ney 1nf0

14563846

S.Parthasarathy, K.Eaazhisai, H.Balaram, P.Balaram, and M.R.Murthy (2003).
Structure of Plasmodium falciparum triose-phosphate isomerase-2-phosphoglycerate complex at 1.1-A resolution.

J Biol Chem, 278, 52461-52470.

PDB code:

1o5x

12454456

S.Parthasarathy, H.Balaram, P.Balaram, and M.R.Murthy (2002).
Structures of Plasmodium falciparum triosephosphate isomerase complexed to substrate analogues: observation of the catalytic loop in the open conformation in the ligand-bound state.

Acta Crystallogr D Biol Crystallogr, 58, 1992-2000.

PDB codes:

1m7o 1m7p

11589711

I.Kursula, S.Partanen, A.M.Lambeir, D.M.Antonov, K.Augustyns, and R.K.Wierenga (2001).
Structural determinants for ligand binding and catalysis of triosephosphate isomerase.

Eur J Biochem, 268, 5189-5196.

PDB code:

1if2

11114510

H.Erlandsen, E.E.Abola, and R.C.Stevens (2000).
Combining structural genomics and enzymology: completing the picture in metabolic pathways and enzyme active sites.

Curr Opin Struct Biol, 10, 719-730.

9684881

J.Sun, and N.S.Sampson (1998).
Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase.

Protein Sci, 7, 1495-1505.

9548921

T.R.Schneider, E.Gerhardt, M.Lee, P.H.Liang, K.S.Anderson, and I.Schlichting (1998).
Loop closure and intersubunit communication in tryptophan synthase.

Biochemistry, 37, 5394-5406.

PDB codes:

1a50 1a5s 2wsy

7849584

C.L.Verlinde, E.A.Merritt, F.Van den Akker, H.Kim, I.Feil, L.F.Delboni, S.C.Mande, S.Sarfaty, P.H.Petra, and W.G.Hol (1994).
Protein crystallography and infectious diseases.

Protein Sci, 3, 1670-1686.

7922037

C.L.Verlinde, and W.G.Hol (1994).
Structure-based drug design: progress, results and challenges.

Structure, 2, 577-587.

8061610

S.C.Mande, V.Mainfroid, K.H.Kalk, K.Goraj, J.A.Martial, and W.G.Hol (1994).
Crystal structure of recombinant human triosephosphate isomerase at 2.8 A resolution. Triosephosphate isomerase-related human genetic disorders and comparison with the trypanosomal enzyme.

Protein Sci, 3, 810-821.

PDB code:

1hti

8356028

M.E.Noble, J.P.Zeelen, and R.K.Wierenga (1993).
Structures of the "open" and "closed" state of trypanosomal triosephosphate isomerase, as observed in a new crystal form: implications for the reaction mechanism.

Proteins, 16, 311-326.

PDB codes:

1tpd 1trd 2v5l

8503454

M.L.Chang, P.J.Artymiuk, X.Wu, S.Hollán, A.Lammi, and L.E.Maquat (1993).
Human triosephosphate isomerase deficiency resulting from mutation of Phe-240.

Am J Hum Genet, 52, 1260-1269.

8431552

R.C.Wade, M.E.Davis, B.A.Luty, J.D.Madura, and J.A.McCammon (1993).
Gating of the active site of triose phosphate isomerase: Brownian dynamics simulations of flexible peptide loops in the enzyme.

Biophys J, 64, 9.

1304889

C.L.Verlinde, C.J.Witmans, T.Pijning, K.H.Kalk, W.G.Hol, M.Callens, and F.R.Opperdoes (1992).
Structure of the complex between trypanosomal triosephosphate isomerase and N-hydroxy-4-phosphono-butanamide: binding at the active site despite an "open" flexible loop conformation.

Protein Sci, 1, 1578-1584.

PDB code:

1tsi

1624956

C.L.Verlinde, G.Rudenko, and W.G.Hol (1992).
In search of new lead compounds for trypanosomiasis drug design: a protein structure-based linked-fragment approach.

J Comput Aided Mol Des, 6, 131-147.

1633802

D.A.Kuntz, R.Osowski, M.Schudok, R.K.Wierenga, K.Müller, H.Kessler, and F.R.Opperdoes (1992).
Inhibition of triosephosphate isomerase from Trypanosoma brucei with cyclic hexapeptides.

Eur J Biochem, 207, 441-447.

1528078

M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.

Med Res Rev, 12, 317-372.

1639191

R.K.Wierenga, T.V.Borchert, and M.E.Noble (1992).
Crystallographic binding studies with triosephosphate isomerases: conformational changes induced by substrate and substrate-analogues.

FEBS Lett, 307, 34-39.

2062827

R.K.Wierenga, M.E.Noble, J.P.Postma, H.Groendijk, K.H.Kalk, W.G.Hol, and F.R.Opperdoes (1991).
The crystal structure of the "open" and the "closed" conformation of the flexible loop of trypanosomal triosephosphate isomerase.

Proteins, 10, 33-49.

PDB codes:

2tim 3tim

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 codes are shown on the right.