DHRS1 Results: Difference between revisions

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A single monomeric unit of DHRS1 contains 13 α helices 1 central β-sheet region consisting of 7 strands.  It is thought to exist biologically as a dimer.
A single monomeric unit of DHRS1 contains 13 α helices 1 central β-sheet region consisting of 7 strands.  It is thought to exist biologically as a dimer.


Dehydrogenase/reductase SDR family member 1 has highly conserved structure compared across the SDR family.
DHRS1 has highly conserved structure compared across the SDR family.


The SDR family is part of the Super Family; NAD(P)-binding Rossmann-fold domain proteins all of which have the Rossmann-fold domain, which is characterised by a central β-sheet surrounded by α-helicies. This puts them in  the Alpha and Beta proteins (α/β) class.
The SDR family is part of the Super Family; NAD(P)-binding Rossmann-fold domain proteins all of which have the Rossmann-fold domain, which is characterised by a central β-sheet surrounded by α-helicies. This puts them in  the Alpha and Beta proteins (α/β) class.
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Some key residues are conserved across the entire family. Notable a Tyrosine that binds NAD(P). It is part of a larger motif [S-x(12)-Y-x(3)-K] that includes two other residues involved in binding NAD(P) (Wu Q, et al 2001).
Some key residues are conserved across the entire family. Notable a Tyrosine that binds NAD(P). It is part of a larger motif [S-x(12)-Y-x(3)-K] that includes two other residues involved in binding NAD(P) (Wu Q, et al 2001).


There is another highly conserved motif (LDVLD) involved in the initial folding of the protein (Wu Q, et al 2001). It forms part of the hydrophobic core most notably a strand of the β-sheet that is part of the Rossmann-fold.  
There are more highly conserved motifs including a [G-x(3)-G-x-G] that is part of a c0-enzyme binding site???? and [LDVLD] involved in the initial folding of the protein (Wu Q, et al 2001). It forms part of the hydrophobic core most notably a strand of the β-sheet that is part of the Rossmann-fold.  





Revision as of 07:08, 3 June 2008

Figure 1
DHRS1 Gene expression pattern. Reproduced from Genomics Institute of Novartis Research Foundation. 2008



Results/Evolution

The phylogenic tree shows a small section of the family is contained in land based higher organisms (Bos taurus through to Mus Muluscus), a smaller section is found in sea based eukaryotes (Danio rerio and Tetraodon nigroviridis) and the majority of the family is round in bacteria. The majority of bacteria found to possess this family are proteobacteria, although there are also gram positive rod (eg. bacillus) and cyanobacteria (eg. anabena). This suggests that this particular family has been present for a long time and has evolved from bacteria, most likely proteobacteria. Blue branches show organisms of the anamalia kingdom, Black branches show organisms of the bacteria kingdom.

Aedes aegypti and Schistosoma japonicum are both found in the anamalia kingdom, although are seperated on the graph. Both of these organisms are parasitic by nature. Aedes aegypti is commonly known as the yellow fever mosquito. Schistosoma japonicum is a parasite and one of the major infectious agents of schistosomiasis.

Figure 4 Unrooted phylogram for Dehydrogenase/reductase (SDR family)


Clustal Alignment

Clustal alignment shows that Homo_sapiens_SDR_family_1 (an exact match for our target protein) with regards to protein sequence, contains all eight key residues (locations 117 - 121, 195,209 and 213). It also contains a sequence K-[A,S]-F-W-E-x-P-A-S at location 138 - 146 which is conserved only between land based animals.

Figure 1
Clustal Alignment of target protein with blast results with marked key residues


The N-terminus region of the clustal alignment shows the main difference between classical SDR's and extended SDR's. There is a highly conserved tail (locatoin 280 - 360) which appears only in some of the results aligned. As our target sequence is in the extended SDR family, most of the sequences aligned are also in the extended SDR family.

Figure 2
Clustal Alignment of the N-terminus region of the target protein


Results/structure

Figure 2
Cartoon of a single DHRS1 unit with different structural features highlighted in different colours.


A single monomeric unit of DHRS1 contains 13 α helices 1 central β-sheet region consisting of 7 strands. It is thought to exist biologically as a dimer.

DHRS1 has highly conserved structure compared across the SDR family.

The SDR family is part of the Super Family; NAD(P)-binding Rossmann-fold domain proteins all of which have the Rossmann-fold domain, which is characterised by a central β-sheet surrounded by α-helicies. This puts them in the Alpha and Beta proteins (α/β) class.

Some key residues are conserved across the entire family. Notable a Tyrosine that binds NAD(P). It is part of a larger motif [S-x(12)-Y-x(3)-K] that includes two other residues involved in binding NAD(P) (Wu Q, et al 2001).

There are more highly conserved motifs including a [G-x(3)-G-x-G] that is part of a c0-enzyme binding site???? and [LDVLD] involved in the initial folding of the protein (Wu Q, et al 2001). It forms part of the hydrophobic core most notably a strand of the β-sheet that is part of the Rossmann-fold.


Figure 3
Cartoon of DHRS1 (cyan/magenta) aligned with 3-Oxoacyl-(Acyl-Carrier-protien)reductase (green/red) the key catalytic Tyrosine residue is shown in as well.


Structure comparison

Comparison of DHRS1 to 3-Oxoacyl-(Acyl-Carrier-protien)reductase its closest structurally related protein, finds that whilst it shares only 27% of its sequence, it is structurally very similar (Fig 2). They share many structural features including the central β-sheet region and many α helices. Key conserved residues such as the tyrosine shown are also in very similar positions eluding to a similar function. Importantly the key catalytic triad (S-Y-K) is still in the same place with the tips of the residues only moved 0.7-3 Angstroms (fig 3).

Figure 4
Close in view of the catalytic triad (S-Y-K)from the alignment 2uvd and DHRS1. Showing the difference in the positions of the key residues.



Table 1

PDB/chain identifiers and structural alignment statistics from DALI search

No:	Chain	Z	rmsd	lali	nres	%id	Description
1:	2qq5-A	48.1	0.0	238	238	100	MOL: DEHYDROGENASE/REDUCTASE SDR1;
2:	2uvd-A	29.6	2.1	220	246	27	MOL: 3-OXOACYL-(ACYL-CARRIER-PROTEIN)  REDUCTASE;             
3:	1yde-F	29.3	2.1	216	256	29	MOL: RETINAL DEHYDROGENASE/REDUCTASE 3;                         
4:	1vl8-B	29.1	2.0	220	252	27	MOL: GLUCONATE 5-DEHYDROGENASE;                                 
5:	2bgk-A	29.0	2.1	219	267	25	MOL: RHIZOME SECOISOLARICIRESINOL DEHYDROGENASE; 
6:	2q2q-D	28.9	2.0	217	255	26	MOL: BETA-D-HYDROXYBUTYRATEDEHYDROGENASE;                                
7:	1rwb-F	28.8	2.2	221	261	24	MOL: GLUCOSE 1-DEHYDROGENASE;                                   
8:	1rwb-A	28.8	2.3	222	261	24	MOL: GLUCOSE 1-DEHYDROGENASE;                                   
9:	1gee-A	28.8	2.3	222	261	24	MOL: GLUCOSE 1-DEHYDROGENASE;                                   
10:	1gco-A	28.8	2.3	222	261	24	MOL: GLUCOSE DEHYDROGENASE;                                     
11:	2zat-A	28.7	2.1	221	251	23	MOL: DEHYDROGENASE/REDUCTASE SDR4;
12:	1gee-B	28.7	2.3	221	261	24	MOL: GLUCOSE 1-DEHYDROGENASE;                                   
13:	1gco-E	28.7	2.3	221	261	24	MOL: GLUCOSE DEHYDROGENASE;







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