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	==3S structures of dihydropteroate synthase==		==3S structures of dihydropteroate synthase==

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Revision as of 09:21, 26 August 2014

spinqualitylabelsall models Dihydropteroate synthase (PDB code 1tws) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Dihydropteroate synthase (DHPS) catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate to para-aminobenzoic acid (PABA) to form 7,8-dihydropteroate. DHPs is a key enzyme in folate synthesis. Folate is necessary for nucleic acid synthesis. DHPS is found in bacteria and not in eukaryotes. Hence, it makes a target to sulfonamide antibiotics. Some DHPS contain a dihydro-6-hydroxymethylpterin pyrophosphokinase domain at their N terminal and are named PPPK-DHPS. Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies [1] Drug resistance has been an urgent problem that severely limits the therapy of current clinical microbial diseases. Sometimes, it generally correlates with mutations to the dihydropteroate synthase (DHPS) gene. In the current study, we focus on the molecular dynamic behaviors and binding free energy calculations of form and B. anthracis dihydropteroate synthase (BaDHPS) to search for the relationship between mutation and drug resistance. Wt-BaDHPS is colored in darkmagenta, mutated D184N complex is in green and K220Q complex is in cyan. After 20ns MD simulations on the , it is obvious that . Only Loop 1, Loop 2 and Loop 7 are colored, ligand DHP-STZ is colored in the same color as the corresponding protein: for Wt-BaDHPS is in darkmagenta, for mutated D184N complex is in green and for K220Q complex is in cyan. Mutation will cause conformational change, which mainly locate on some loop region around the binding site (Loop 1, Loop 2 and Loop 7). These results may be helpful for further drug resistance and de novo drug design investigations.

Contents 1 3S structures of dihydropteroate synthase 1.1 DHPS 1.2 DHPS binary complexes 1.3 DHPS ternary complexes 1.4 Bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophsphokinase-DHPS

3S structures of dihydropteroate synthase

Updated on 26-August-2014

DHPS

1ad1, 4hb7 – SaDHPS - Staphylococcus aureus
1ajz – EcDHPS – Escherichia coli
1tws, 3v5o – BaDHPS – Bacillus anthracis
2dqw - TtDHPS – Thermus thermophilus
2vef - SpDHPS – Streptococcus pneumonia
2vp8 – MtDHPS – Mycobacterium tuberculosis
2y5j – BcDHPS – Burkholderia cenocepacia
3tzn – YpDHPS – Yersinia pestis

DHPS binary complexes

1ad4 – SaDHPS + pterin-pyrophosphate
1aj2 – EcDHPS + dihydro-pterin-methanyl-phosphonophosphate
1eye - MtDHPS + pterin-methyl-phosphate
1tww - BaDHPS + hydroxymethylpterin-diphosphate
1twz - BaDHPS + pterin-methyl-phosphate
1tx0 - BaDHPS + pteroic acid
1tx2, 3h21, 3h22, 3h23, 3h24, 3h26, 3h2a, 3h2c, 3h2e, 3h2f, 3h2m, 3h2n, 3h2o, 4d8z, 4d9p, 4dai, 4db7, 4d8a, 4daf - BaDHPS + inhibitor
2dza - TtDHPS + PABA
2dzb - TtDHPS + hydroxymethylpterin-diphosphate
2veg - SpDHPS + pterin-methyl-phosphate
2y5s - BcDHPS + dihydro-pteroate
3tya - BaDHPS + dihydro-pteroate
3tyc - BaDHPS + amino-hydroxymethyl-dihydro-pteridinone
3tr9 - DHPS + pteroic acid – Coxiella burnetii
3tyu – YpDHPS + pteroic acid

DHPS ternary complexes

1aj0 – EcDHPS + sulfanilamide + amino-methyldiene-dihydro-pteridinone
3tyb - BaDHPS + hydroxybenzoic acid + amino-hydroxymethyl-dihydro-pteridinone
3tyd - BaDHPS + pyrophosphate+ amino-hydroxymethyl-dihydro-pteridinone
3tye - BaDHPS + sulfa derivative + amino-hydroxymethyl-dihydro-pteridinone
3tyz - YpDHPS + pyrophosphate + PABA + amino-hydroxymethyl-dihydro-pteridinone
3tzf - YpDHPS + sulfa derivative + hydroxymethylpterin-diphosphate

Bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophsphokinase-DHPS

3mcm, 3mcn – FtPPPK-DHPS – Francisella tulerensis
3mco - FtPPPK-DHPS + amino-hydroxymethyl-dihydro-pteridinone + methyladenosine triphosphate
2bmb - PPPK-DHPS + pterin-methyl-phosphate - yeast

References

1. ↑ Chu WT, Zhang JL, Zheng QC, Chen L, Xue Q, Zhang HX. Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies. J Biomol Struct Dyn. 2012 Oct 2. PMID:23030549 doi:10.1080/07391102.2012.726529