Homo sapiens · seed P00374 · 187 aa · family defined as ≥30% identity to that seed · compiled 07 October 2026
Open in CODSWALLOP UniProt P00374 RCSB by accession PDBe-KB AlphaFold DB InterPro CATH 3.40.430.10 SCOP 8040487 SCOP 8032732 SCOP 8041552 SCOP 8068933 SCOP 8032748 SCOP 8068941 SCOP 8077793 SCOP 8101343 SCOP 8032717 SCOP 8032249 SCOP 8093486 SCOP 8032720 RCSB 1BOZ PDBe
CATH and SCOP identifiers come from the RCSB's own structure annotations, which the Domains panel already reads, so these are looked up rather than guessed at.
Every figure here is counted over the whole family rather than quoted from one entry.
1BOZ, the structure every other member of this family is superposed onto. Rendered by the RCSB and embedded here: the live app shows an interactive viewport, which a document that fetches nothing cannot.
How many of this family's constructs contain each residue of the seed. A trough is a stretch nobody has put in a construct, which is a construct-design answer rather than a disorder one.
96 distinct constructs across 402 entries. 250 polymer entities differ from the UniProt canonical sequence in some way, 82 carry a recognised expression tag and 0 carry a fusion partner.
"Differs from canonical" is not the same as "engineered". The canonical sequence is the full gene product, so a secreted protein whose structures all start after its signal peptide counts every one of them as different: lysozyme's most-used construct, residues 19–147 on 1,239 entities, is simply the mature protein. Read the construct column below for what was actually done, rather than this count.
| Entities | Length | Best (Å) | Best entry | What was made |
|---|---|---|---|---|
| 50 | 186 | 1.05 | 1KMV | residues 2-187 |
| 27 | 179 | 1.20 | 5SD5 | His6; Thrombin site; M1S, T2H |
| 22 | 608 | 1.97 | 6KP7 | matches the canonical sequence |
| 21 | 206 | 1.45 | 3NZB | matches the canonical sequence |
| 20 | 161 | 1.40 | 6DDW | matches the canonical sequence |
| 19 | 187 | 1.20 | 4M6J | matches the canonical sequence |
| 19 | 521 | 2.53 | 6PF8 | matches the canonical sequence |
| 14 | 192 | 1.60 | 1AOE | S2L, K84E |
| 13 | 159 | 1.49 | 6DDP | residues 3-161 |
| 13 | 173 | 1.10 | 8F80 | His6; C89S, E96A |
| 10 | 608 | 2.20 | 6A2M | matches the canonical sequence |
| 9 | 162 | residues 2-163 | ||
| 9 | 227 | 1.60 | 3CSE | His8 |
| 8 | 189 | 1.70 | 8DFR | matches the canonical sequence |
| 8 | 566 | 2.20 | 4EIL | 2 internal deletions |
| 7 | 166 | 2.10 | 4ELG | Thrombin site |
| 6 | 610 | 2.05 | 7FGX | matches the canonical sequence |
| 5 | 521 | 1.80 | 5T7O | matches the canonical sequence |
| 5 | 521 | 2.40 | 2H2Q | H32R, L55V, R137Q |
| 4 | 165 | 1.90 | 3S9U | I2R |
| 4 | 168 | 2.08 | 3JWK | His6; I2R, Y102F |
| 4 | 178 | 1.90 | 3TQ8 | His10; TEV site |
| 4 | 186 | 1.40 | 3D80 | residues 2-187 |
| 4 | 204 | 1.65 | 9Y7U | matches the canonical sequence |
| 4 | 208 | 1.30 | 8CRH | matches the canonical sequence |
Showing the 25 most-used of 96.
Columns where the wild-type residue still dominates but a real minority carries something else, which is a different question from "what varies across species".
| Oligomeric state | Chains | Entries | Share |
|---|---|---|---|
| monomeric | 1 | 292 | 72.6% |
| dimeric | 2 | 105 | 26.1% |
| tetrameric | 4 | 5 | 1.2% |
272 entries have the depositor's assembly corroborated by PISA, 127 carry the depositor's word alone and 3 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run. 28 entries carry more than one assembly with different chain counts, so they have no single answer to quote: 1DR1, 1DR2, 1DR3, 1DR4, 2H2Q, 3CL9, 3S3V, 4KY8, 4Q0E, 5UJF, 6NNC, 6NND, 6NNE, 6NNH, 6NNI, 6VS5, 6VS6, 6VS8, 6VS9, 6VSD.
Every source's own domains on the seed axis, one row each. They are not merged: Pfam, CATH, SCOP and InterPro disagree about boundaries, and a merged track would state a consensus none of them gave.
| Domain | Source | Span (seed) | Chains |
|---|---|---|---|
| Dihydrofolate Reductase, subunit A | CATH 3.40.430.10 | 8–187 | 307 |
| Dihydrofolate reductase-like | SCOP2B 8040487 | 2–187 | 88 |
| Dihydrofolate reductase-like | SCOP2B 8032732 | 2–187 | 7 |
| Dihydrofolate reductase-like | SCOP2B 8041552 | 4–187 | 14 |
| Dihydrofolate reductase-like | SCOP2B 8068933 | 5–187 | 4 |
| Dihydrofolate reductase-like | SCOP2B 8032748 | 8–187 | 16 |
| Dihydrofolate reductase-like | SCOP2B 8068941 | 11–172 | 22 |
| Dihydrofolate reductase-like | SCOP2B 8077793 | 11–187 | 11 |
| Dihydrofolate reductase-like | SCOP2B 8101343 | 14–176 | 18 |
| Dihydrofolate reductase-like | SCOP2B 8032717 | 17–178 | 9 |
| Dihydrofolate reductase-like | SCOP2B 8032249 | 17–187 | 9 |
| Dihydrofolate reductase-like | SCOP2B 8093486 | 19–177 | 4 |
NDP244 entries
NAP108 entries
UMP57 entries
MTX34 entries
FOL20 entries
UFP16 entries
TOP14 entries
CB313 entries
CP610 entries
MMV9 entries
1CY6 entries
DH15 entries
| Component | Class | Name | Entries | Best (Å) |
|---|---|---|---|---|
| NDP | cofactor | Nadph Dihydro-Nicotinamide-Adenine-Dinucleotide Phosphate | 244 | 1.05 |
| NAP | cofactor | Nadp Nicotinamide-Adenine-Dinucleotide Phosphate | 108 | 0.92 |
| SO4 | ion | Sulfate Ion | 84 | 0.92 |
| UMP | ligand | 2'-Deoxyuridine 5'-Monophosphate | 57 | 1.80 |
| EDO | cryoprotectant | 1,2-Ethanediol | 42 | 1.10 |
| GOL | cryoprotectant | Glycerol | 41 | 1.10 |
| MTX | ligand | Methotrexate | 34 | 1.70 |
| PO4 | ion | Phosphate Ion | 30 | 1.69 |
| CL | ion | Chloride Ion | 30 | 1.25 |
| CO | ion | Cobalt (Ii) Ion | 24 | 1.52 |
| FOL | cofactor | Folic Acid | 20 | 0.93 |
| CA | ion | Calcium Ion | 19 | 1.70 |
| UFP | ligand | 5-Fluoro-2'-Deoxyuridine-5'-Monophosphate | 16 | 2.53 |
| TOP | ligand | Trimethoprim | 14 | 1.40 |
| CB3 | ligand | 10-Propargyl-5,8-Dideazafolic Acid | 13 | 2.20 |
| CP6 | ligand | 5-(4-Chloro-Phenyl)-6-Ethyl-Pyrimidine-2,4-Diamine | 10 | 1.30 |
| MMV | ligand | 3-(2-{3-[(2,4-Diamino-6-Ethylpyrimidin-5-Yl)oxy]propoxy}phenyl)p | 9 | 0.92 |
| MES | buffer | 2-(N-Morpholino)-Ethanesulfonic Acid | 8 | 1.56 |
| 1CY | ligand | 1-(4-Chlorophenyl)-6,6-Dimethyl-1,6-Dihydro-1,3,5-Triazine-2,4-D | 6 | 1.52 |
| DH1 | ligand | 2,4-Diamino-5-[2-Methoxy-5-(4-Carboxybutyloxy)benzyl]pyrimidine | 5 | 1.23 |
Parsed from the free text 365 depositors typed into
_exptl_crystal_grow.pdbx_details, out of 370
entries that recorded anything at all.
Median pH 6.8
(range 4.0 to 9.5).
402 entries carry a wwPDB validation report: 147 clean, 122 worth a check and 133 with something to explain. Median clashscore 7.31, median RSRZ outliers 2.75%, median R-free minus R-work 0.043. 362 have released structure factors.
| Organism | Entries | Best (Å) | Ligand-bound | Seed covered |
|---|---|---|---|---|
| Homo sapiens | 89 | 1.05 | 88 | 100% |
| Plasmodium falciparum | 37 | 1.97 | 37 | 91% |
| Mycobacterium tuberculosis H37Rv | 35 | 1.20 | 35 | 59% |
| Pneumocystis carinii | 24 | 1.45 | 24 | 79% |
| Mycobacterium tuberculosis | 23 | 1.23 | 23 | 59% |
| Cryptosporidium hominis | 23 | 2.53 | 23 | 98% |
| Mycobacterium ulcerans Agy99 | 19 | 0.92 | 19 | 80% |
| Candida albicans | 17 | 1.60 | 17 | 76% |
| Bacillus anthracis | 16 | 1.65 | 15 | 95% |
| Toxoplasma gondii | 14 | 2.05 | 14 | 95% |
| Nakaseomyces glabratus | 10 | 1.60 | 10 | 80% |
| Lacticaseibacillus casei | 10 | 1.70 | 9 | 74% |
187 residues, numbered every ten. Every identity figure in this document is measured against this sequence.
active or binding site modified residue or glycosylation disulphide cysteine transmembrane or signal the 15 most-substituted positions
Sites are UniProt's curated features where the seed is a UniProt accession; the substituted positions are measured from this family's own alignment rather than annotated, and only the fifteen most substituted are marked: every position carrying a minority substitution would be most of the protein, because the family holds orthologues. A residue can carry more than one and is drawn with the first that applies, in the order of the key above.
One record per paper, not per entry.
| Year | Citation |
|---|---|
| 2026 | Evolutionary Convergence on a Dihydrofolate Reductase Mutation Drives Trimethoprim-Sulfamethoxazole Resistance in Burkholderia thailandensis. Acs Infect Dis. doi:10.1021/acsinfecdis.5c01132 |
| 2026 | Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2026.118863 |
| 2025 | A virtual screening strategy to repurpose antifolate compounds as W.bancrofti DHFR inhibitors. Bioorg.Med.Chem.Lett. doi:10.1016/j.bmcl.2025.130370 |
| 2025 | Structural insights into a plant-conserved DHFR-TS reveal a selective herbicide target. Mol Plant doi:10.1016/j.molp.2025.06.016 |
| 2024 | Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium , Two Emerging Human Pathogens. J.Med.Chem. doi:10.1021/acs.jmedchem.4c01594 |
| 2024 | Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors. Bioorg.Chem. doi:10.1016/j.bioorg.2024.107789 |
| 2024 | Novel flexible biphenyl Pf DHFR inhibitors with improved antimalarial activity. Rsc Med Chem doi:10.1039/d4md00197d |
| 2024 | Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti- Trypanosoma brucei Agents. Acs Infect Dis. doi:10.1021/acsinfecdis.4c00113 |
| 2023 | Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris. Acta Crystallogr D Struct Biol doi:10.1107/S2059798323004709 |
| 2023 | Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy. Rsc Med Chem doi:10.1039/d3md00242j |
| 2023 | Crystal structure of dihydrofolate reductase from the filarial nematode W. bancrofti in complex with NADPH and folate. Plos Negl Trop Dis doi:10.1371/journal.pntd.0011303 |
| 2022 | Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase. Acs Chem.Biol. doi:10.1021/acschembio.1c00627 |
| 2022 | MANORAA: A machine learning platform to guide protein-ligand design by anchors and influential distances. Structure doi:10.1016/j.str.2021.09.004 |
| 2021 | Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening. J Enzyme Inhib Med Chem doi:10.1080/14756366.2020.1854244 |
| 2020 | Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase fromMycobacterium tuberculosis. Acs Infect Dis. doi:10.1021/acsinfecdis.0c00263 |
| 2020 | The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. J.Med.Chem. doi:10.1021/acs.jmedchem.0c00546 |
| 2020 | Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2020.112263 |
| 2020 | Targeting the TS dimer interface in bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa: Virtual screening identifies novel TS allosteric inhibitor Bioorg.Med.Chem.Lett. doi:10.1016/j.bmcl.2020.127292 |
| 2019 | Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents. Cell Chem Biol doi:10.1016/j.chembiol.2019.02.013 |
| 2019 | Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. Acta Crystallogr D Struct Biol doi:10.1107/S205979831900901X |
| 2019 | 6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum. Bioorg.Med.Chem. doi:10.1016/j.bmc.2019.115158 |
| 2019 | Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2019.111673 |
| 2019 | Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis. J. Med. Chem. doi:10.1021/acs.jmedchem.8b01754 |
| 2019 | Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase. Febs Lett. doi:10.1002/1873-3468.13474 |
| 2018 | Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance. ACS Med Chem Lett doi:10.1021/acsmedchemlett.8b00389 |
| 2017 | Structure and kinetics assays of recombinant Schistosoma mansoni dihydrofolate reductase. Acta Trop. doi:10.1016/j.actatropica.2017.03.007 |
| 2016 | Protein rethreading: A novel approach to protein design. Sci Rep doi:10.1038/srep26847 |
| 2016 | Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis. Plos One doi:10.1371/journal.pone.0161740 |
| 2016 | Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design. ACS Med Chem Lett doi:10.1021/acsmedchemlett.6b00328 |
| 2015 | Structure-activity correlations for three pyrido[2,3-d]pyrimidine antifolates binding to human and Pneumocystis carinii dihydrofolate reductase. Acta Crystallogr F Struct Biol Commun doi:10.1107/S2053230X15008468 |
| 2015 | Structural genomics for drug design against the pathogen Coxiella burnetii. Proteins doi:10.1002/prot.24841 |
| 2014 | Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs. Structure doi:10.1016/j.str.2013.09.022 |
| 2014 | Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata. J.Med.Chem. doi:10.1021/jm401916j |
| 2014 | The Structure and Competitive Substrate Inhibition of Dihydrofolate Reductase from Enterococcus faecalis Reveal Restrictions to Cofactor Docking. Biochemistry doi:10.1021/bi401104t |
| 2014 | Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. Bioorg.Med.Chem.Lett. doi:10.1016/j.bmcl.2014.07.049 |
| 2013 | Divergent evolution of protein conformational dynamics in dihydrofolate reductase. Nat.Struct.Mol.Biol. doi:10.1038/nsmb.2676 |
| 2013 | Kinetic and structural analysis for potent antifolate inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and human dihydrofolate reductases and their active-site variants. Antimicrob.Agents Chemother. doi:10.1128/AAC.00172-13 |
| 2013 | Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase. Biochemistry doi:10.1021/bi400852h |
| 2013 | Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3-d]pyrimidine Analogues As Antifolates; Application of Buchwald-Hartwig Aminations of Heterocycles. J.Med.Chem. doi:10.1021/jm400086g |
| 2013 | Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.1307130110 |