Dihydrofolate reductase

From Proteopedia

Revision as of 09:43, 25 February 2014

spinqualitylabelsall models DHFR complex with phosphate (PDB code 3ia5) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Image:DHFR.png Crystal structure of Moritella profunda dihydrofolate reductase, 3ia5 Dihydrofolate reductase (DHFR) is an enzyme which uses the co-factor NADPH as electron donor which converts it to NADP. It catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid (folate). The folate is a form of the essential vitamin B9. Antifolate inhibitors like methotrexate are used in cancer therapy. Trimethoprim (TMP) is a known inhibitor of DHFR. DHFR forms a complex with thymidylate synthase (TS). Both enzymes participate in the biosymthesis of pyrimidine. For more details see Molecular Playground/DHFR Malarial Dihydrofolate Reductase as Drug Target Methotrexate. Structure and Function DHFR is a ubiquitous enzyme found in all organisms. The primary physiological role of DHFR is maintenance of the intracellular levels of tetrahydrofolate, a precursor of cofactors required for the biosynthesis of purines, pyrimidines, and several amino acids. The enzyme, which is the sole source of tetrahydrofolate catalyzes the reduction of (DHF) to 5,6,7,8-tetrahydrofolate (THF) by stereospecific hydride transfer from the cofactor to the C6 atom of the pterin ring with concomitant protonation at N5. Being the sole source of THF it is an Achilles’ heel of rapidly proliferating cells, making it an attractive target of several important anticancer and antimicrobial drugs such as methotrexate, trimethoprim, and pyrimethamine. E. coli DHFR is a small (18 kD) protein with an α/β structure consisting of a central eight-stranded β-sheet and four flanking α-helices. The active site cleft divides the protein into two structural subdomains: the (red) and the (green). The adenosine binding subdomain is the smaller of the two subdomains and provides the binding site for the adenosine moiety of the cofactor. The major subdomain consists of ~100 residues from the N and C termini and is dominated by a set of three loops on the ligand binding face that surround the active site. In terms of sequence length, these loops make up approximately 40%–50% of the major subdomain; hence it is sometimes called the “loop” subdomain. The loops are termed Met20, F-G, and G-H loops. Hinge bending motions about Lys38 and Val88 allow the adenosine binding domain to move relative to the major domain upon binding of various ligands, resulting in closure of the active site cleft. A movie depicting the conformational changes of DHFR during one turnover of substrate has been constructed by M. R. Sawaya and J. Kraut using six isomorphous crystallographic structures. http://chem-faculty.ucsd.edu/kraut/dhfr.html

Additional Resources

• For additional information, see: Cancer.
• See also Molecular Playground/DHFR.

3D Structures of Dihydrofolate reductase

Updated on 25-February-2014

DHFR

1ohk, 1ohj – hDHFR – different crystal forms - human
3f8y, 3f8z, 3f91, 3eig, 1dlr, 1dls – hDHFR (mutant)
3ia5 – MpDHFR – Mritella profunda
2kgk, 2qk8 – BaDHFR – Bacillus anthracis
3dfr – LcDHFR – Lactobacillus casei
2w9t – SaDHFR S1 - Staphylococcus aureus
2ith, 1vdr – HvDHFR - Haloferax volcanii
2rh2, 2gqv, 1vie, 1vif, 1dfr, 5dfr – EcDHFR – Eschericia coli
1dhi, 1dhj, 2d0k – EcDHFR (mutant)
3sfm – EcDHFR-2
1dyr – PncDHFR - Pneumocystis carinii
1zdr – BsDHFR – Bacillus stearothermophilus
1juv – DHFR – Bacteriophage T4
1ai9 – CaDHFR - Candida albicans
1cz3, 1d1g – DHFR – Thermotoga maritima
3q1h – DHFR – Yersinia pestis
2l28 – DHFR – Lactobacillus casei - NMR
3vco – DHFR – Schistosoma mansoni

DHFR-Thymidine synthase (TS) complex

3cl9, 2h2q, 3qfx – TcDHFR-TS - Trypanosoma cruzi
1qzf - ChTcDHFR-TS – Cryptosporidium hominis
3dl5, 3dl6, 2oip – ChDHFR-TS (mutant)
3i3r, 3kjr - BbDHFR-TS – Babesia bovis
3clb – TcDHFR-TS + TMX
3irm, 3iro - TcDHFR-TS + inhibitor
3irn - TcDHFR-TS+NADPH +inhibitor
3dg8, 1j3i, 3dga - PfDHFR-TS+NADPH +dUMP+inhibitor – Plasmodium falciparum
1j3k, 1j3j, 3jsu - PfDHFR-TS (mutant)+NADPH+dUMP+ inhibitor
3qgt - PfDHFR-TS +NADPH+dUMP+ inhibitor
3qg2 - PfDHFR-TS (mutant)+NADPH + inhibitor
3um5, 3um6, 4dp3 - PfDHFR-TS (mutant)+NADPH + dUMP + anti-malarial drug
3um8, 4dph - PfDHFR-TS + NADPH + anti-malarial drug
4dpd - PfDHFR-TS +NADPH + dUMP + folate
3inv - TcDHFR-TS+NADPH+dUMP+inhibitor
3kjs, 3rg9 - TcDHFR-TS+NADPH +inhibitor
3k2h, 3nrr - BbDHFR-TS+NADPH+dUMP+inhibitor
2bl9, 2bla, 2blb, 2blc – PvDHFR-TS+ anti-malarial drug – Plasmodium vivax
3hbb – TcDHFR-TS+MTX & TMTX
4eck, 4eil - DHFR-TS + NADPH + dUMP + folate – Toxoplasma gondii
4ky8 - ChDHFR-TS + NADPH + dUMP + MTX + pyrimidine derivative

DHFR+antifolate inhibitors

Binary complexes

3fra – SaDHFR (mutant)+iclaprim
3sqy, 3sr5, 3srq, 3srr, 3srs, 3sru, 3srw, 4fgg, 4fgh – SaDHFR + inhibitor
3fl8 – BaDHFR+RAB1
3fl9 – BaDHFR+TMP
4elb, 4ele, 4elf, 4elg, 4elh – BaDHFR + inhibitor
2w9h – SaDHFR+TMP
2hm9 – LcDHFR+TMP
1ao8 - LcDHFR+MTX – NMR
1dis, 1diu - LcDHFR+ brodimoprim – NMR
1dra, 1drb, 2drc, 3drc, 1dds, 4dfr - EcDHFR+MTX
2inq – EcDHFR+MTX – neutron diffraction
1rx5, 3och - EcDHFR+ inhibitor
4eig, 4eiz – EcDHFR + antibody fragment
1s3u, 1s3v, 1s3w – hDHFR+tetrahydroauinazoline
1mvs, 1mvt, 1pd8, 1pd9, 1pdb, 1mvs, 1mvt, 3fs6, 1hfp, 1hfq, 1hfr, 2c2s, 2c2t, 2w3b, 3gyf, 3nxo, 3nxr, 3nxt, 3nxv, 3nu0, 4g95 – hDHFR+pyrimidine derivatives
3s7a - hDHFR+ inhibitor
3l3r, 3gi2, 3ghc, 3ghv, 3ghw, 3oaf – hDHFR (mutant)+pyrimidine derivatives
3n0h, 3s3v – hDHFR (mutant) +TMP
2cig – MtDHFR+isoniazid derivative – Mycobacterium tuberculosis
4klx - MtDHFR + ADP
3tq8 - CbDHFR+TMP – Coxiella burnetii
3tq9 – CbDHFR + methotrexate

Ternary complexes

3i8a, 3f0q, 3f0s, 3f0v, 3f0x, 3f0b, 3f0u, 3fq0, 3fqc, 3fqf, 3fqo, 3fqv, 3fqz – SaDHFR (mutant)+NADPH+ pyrimidine derivative
4lae, 4lag, 4lah, 4lek - SaDHFR +NADPH+ quinazoline derivative
3frf – SaDHFR (mutant)+iclaprim+NADPH
3frb – SaDHFR (mutant)+TMP+NADP
3fre, 2w9s – SaDHFR (mutant)+TMP+NADPH
4g8z - DHFR (mutant)+TMP+NADPH – Pneumocystis jirovecii
2w3v – MaDHFR +TMP+NADPH – Mycobacterium avium
2w3w – MaDHFR+NADPH+6-((2,5-diethoxyphenyl)aminomethyl)-2,4-diamino-methylpyrido(2,3-D)pyrimidine
3fy8, 3fyw – SaDHFR + AR-101+NADPH
3fy9 – SaDHFR (mutant)+ AR-102+NADPH
3fyv – SaDHFR (mutant)+ AR-102+NADPH
3fyw – SaDHFR + AR-101+NADPH
3ia4 – MpDHFR+methotrexate (MTX)+NADPH
3jw3, 3jw5 – BaDHFR (mutant)+ TMP +NADPH
3s9u, 3sa1, 3sa2, 3sai – BaDHFR (mutant) +TMP analog + NADP
3dat - BaDHFR+ MTX+NADPH
3e0b, 3jvx, 3jwc, 3jwf, 3jwk, 3jwm – BaDHFR (mutant)+NADP+ pyrimidine derivative
3lg4 - SaDHFR (mutant)+NADP+ pyrimidine derivative
3sgy, 3sh2 - SaDHFR +NADP+ pyrimidine derivative
2w9g - SaDHFR+ TMP +NADPH
3m08 - SaDHFR+RAB1+NADP
3m09 – SaDHFR (mutant)+RAB1+NADP
1lud - LcDHFR+NADPH+ TMP – NMR
1bzf - LcDHFR+NADPH+ TMX – NMR
3cse, 3eej, 3eek, 3eel, 3eem, 4h98 - CgDHFR +NADPH+ pyrimidine derivatives – Candida glabrata
3k45, 3k47 – mDHFR+E & Z-isomer+NADPH – mouse
3d80, 3d84 – mDHFR+NADPH+2,4-diamino-6-(2’-hydrosydibenz[b,f]azepin-5-yl)methylpteridine
2fzi, 2fzj - mDHFR+NADPH+ TMP
1u70 – mDHFR (mutant)+MTX+NADPH
1dre, 1rb3, 1rg7, 1rh3, 1ra3, 1rx3, 3dau, 4gh8 - EcDHFR+NADP+MTX
3kfy - EcDHFR+NADPH + inhibitor
1ddr - EcDHFR+MTX+urea
1tdr - EcDHFR+MTX+Te
1rc4, 1dyj - EcDHFR+NADP+5,10-dideazatetrahydrofolate
1dyh - EcDHFR+NADP+dideazafolic acid
1rx4 - EcDHFR+5,10-dideazatetrahydrofolate+monophosphoadenosine 5’-diphosphoribose
1rx6 - EcDHFR+5,10-dideazatetrahydrofolate+NADPH
1drh - EcDHFR+5]], [[10-dideazatetrahydrofolate+folate+5-deazafolate
2ano, 2anq - EcDHFR+NADPH+MS-SH08-17
3qyl, 3qyo, 3r33 - EcDHFR +NADPH+quinazoline derivative
1vj3 – PcHDFR+TAB+NADPH – Plasmodium carinii
1daj, 3nz6, 3nz9, 3nzb, 3nzc, 3nzd, 4ixe– PcDHFR + NADPH + pyrimidine derivative
4ixf, 4ixg – PcDHFR (mutant) + NADPH + pyrimidine derivative
2fzh – PcDHFR+NADPH+ TMP
1ly3, 1s3y – PcDHFR +NAP+quinazoline derivative
1ly4, 3td8 - PcDHFR +NAP+pyrimidine derivative
2w3a – hDHFR +TMP+NADPH
4ddr, 4kak, 4kbn, 4kd7, 4keb, 4kfj – hDHFR + NADPH + pyrimidine inhibitor
1yho - hDHFR+NADPH+ TMP – NMR
1u71, 1u72 - hDHFR (mutant)+MTX+NADPH
1boz – hDHFR (mutant)+NADPH+quinazoline derivative
1kms, 1kmv , 3ntz, 3nxx, 3nxy – hDHFR+NADPH+ inhibitor
1m79, 1m78, 1m7a, 1ia1, 1ia2, 1ia3, 1ia4, 1aoe – CaDHFR+NADPH+quinazoline derivative
4h95, 4h96, 4h97 - CaDHFR + NADPH + pyrimidine derivative
1df7 - MtDHFR +MTX+NADPH
1dg5 - MtDHFR + TMP +NADPH
4km2 - MtDHFR + ADP + TMP
4kne - MtDHFR + ADP + anti-folate drug
1dg7 - MtDHFR + 4-Br-WR99210 +NADPH
4km0 – MtDHFR + ADP + pyrimidine derivative
1dr1, 1dr2, 1dr3 - cDHFR+NADP+biopterin – chicken
1dr4, 1dr5, 1dr6, 1dr7 - cDHFR+NADP+biopterin+Hg
1klk – DHFR+NADPH+PT653 – rat
1sej - ChDHFR +NADPH+quinazoline derivative+deoxyuridine
3ix9 – DHFR (mutant) +MTX+NADPH – Streptococcus pneumoniae
3nza - PncDHFR+NADPH+ inhibitor

DHFR+ligands

3frd – SaDHFR (mutant)+folate +NADP
2w3m, 4m6k – hDHFR +folate+NADPH
1drf - hDHFR +folate
1dhf, 2dhf – hDHFR+folate+5-deazofolate
4m6l - hDHFR+folate+ NADPH + folate derivative
1e26 - PcDHFR-TS+NADP+folate
2jyb – HvDHFR+folate
2rk1 – EcDHFR+NADP+dihydrofolate
7dfr - EcDHFR+NAP+NADP+folate
1ra8, 1rx8 – EcDHFR+folate+monophosphoadenosine 5’-diphosphoribose
1rb2, 1rx2, 1ra2, 3ql3, 4kjj, 4kjk, 4nx6, 4nx7 - EcDHFR+folate +NADP
3ql0, 4kjl – EcDHFR (mutant) +folate+NADP
1rx7, 1rd7, 1re7 - EcDHFR+folate
1rf7 - EcDHFR+dihydrofolate
1dyi - EcDHFR+NADP+folic acid
4ej1, 4fhb – EcDHFR + antibody fragment + folate
1jol, 1jom - EcDHFR+folinic acid
3jtw – DHFR + ligand – Pediococcus pentosaceus
2cd2, 3cd2, 4cd2 - PcDHFR+NADP+folate
1cd2 - PcHDFR+folate+NADPH
2zza – MpDHFR+ folate +NADP
3tqb – CbDHFR + NADPH + folate

DHFR+co-factors

2hqp, 2lf1 – LcDHFR+NADPH – NMR
2rk2, 2p4t, 1ra9, 1rx9 – EcDHFR+NADP
1rx1, 1ra1 - EcDHFR+NADPH
6dfr - EcDHFR+NAP+NADP
1dg8, 4kl9 - MtDHFR +NADPH
8dfr - cDHFR +NADPH
3tqa – CbDHFR + NADPH
4m6j - hDHFR +NADPH
3k74, 4i13, 4i1n – EcDHFR+nanobody