KpATCC43816 Protein target profile

2-isopropylmalate synthase

Accession: VK055_4499

Gene: leuA2 AIK83038.1 3D evidence: AlphaFold DB model + ColabFold model Metabolism 1 reaction UniProt A0A0H3H1U7
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Length 558
Pocket druggability (P2Rank · AlphaFold DB model) 0.708
Metabolic reactions 1
Chokepoint No
Direct ligand evidence 0 28 total records
Functional annotation 1 EC 8 GO
Target summary

Promising target candidate with multiple supporting evidence streams.

Automated synthesis of the evidence currently loaded. Review the underlying records before prioritizing this protein.

Main supporting evidence

Central metabolic position More central than 96.1% of genes in this genome. No similar human protein detected The current BLAST sequence screen did not find a significant human match, lowering apparent off-target risk. Core gene across strains Marked as conserved by both pan-genome tools: Roary and CoreCruncher. Second pocket predictor agrees P2Rank predicted binding-site probability 0.71. Review the complete evidence below

Risks to review

Microbiome similarity 129 of 4744 screened genomes (2.7%) have a significant similarity hit. This target also has a predicted binding pocket (P2Rank 0.71) — check the ligand evidence before deprioritizing on off-target risk alone. Weak predicted binding pocket FPocket selected-pocket score 0.29.

Evidence coverage

Core evidence streams are available for this target.
Terms and data sources used on this page

PDB: experimentally determined structures from the Protein Data Bank. These are the strongest structural evidence, but may cover only part of the protein.

AlphaFold DB model: a precomputed predicted structure downloaded from AlphaFold Database/UniProt, not an experiment performed here.

ColabFold model: a predicted structure generated for this workspace; interpret it with coverage and confidence.

pLDDT: confidence score for predicted structures. High values support local geometry; low values mean the region should not drive pocket interpretation.

FPocket / P2Rank: software tools that predict possible ligand-binding pockets on a 3D structure. They are useful screening signals, not experimental validation.

Druggability: a pocket-based estimate of whether a small molecule could bind productively. It does not mean a drug already exists.

PDB ligand: a compound observed in an experimental structure. Direct same-protein records are stronger than homolog-transferred records.

ChEMBL: a public database of measured compound bioactivity. Direct entries are stronger than entries transferred from similar proteins.

ZINC: a purchasable-compound database. Here it marks proposed candidates from chemical similarity, not measured binders.

LigQ / LigQ_2: an internal Target pipeline step that gathers PDB, ChEMBL, and ZINC ligand evidence for each protein.

Off-target: sequence similarity to proteins we prefer not to hit, such as human proteins or beneficial gut microbiome proteins.

DEG: Database of Essential Genes. A match suggests the protein resembles genes known to be essential in other organisms.

Roary / CoreCruncher: pan-genome tools used to decide whether a gene is core across analyzed strains or accessory/strain-specific.

EC / GO: functional annotations: EC describes enzyme reactions; GO describes biological process, molecular function, or cellular component.

KEGG pathway: a curated metabolic route label used here to group reactions imported from the metabolic model.

Chokepoint: a metabolic reaction that is the only producer or consumer of a metabolite in the imported model.

Prioritization evidence

Selectivity, essentiality, structural confidence, conservation, and predicted binding-site evidence.

Off-target risk

Human off-target
No hit
Gut microbiome similarity
2.7% of screened genomes Lower prevalence suggests narrower overlap with the screened gut microbiome.

Essentiality

Essential (DEG)
Y
DEG identity (%)
49.72 Higher values support similarity to known essential genes.
DEG E-value
0.0 Smaller values mean stronger essential-gene similarity.

Structure confidence

ColabFold pLDDT
92.72 0-100 confidence; >70 supports local structural interpretation.

Binding-site evidence

AlphaFold DB / UniProt model

P2Rank's binding-site probability is the primary druggability signal shown across the app; FPocket's druggability score is shown alongside it for comparison. Both estimate small-molecule pocket quality after applying the curated structure priority — neither is experimental binding evidence. The 3D viewer may show a different loaded structure, so visible pockets can differ.

Druggability (P2Rank) 0.708
Structure A0A0H3H1U7
Pocket Pocket 1
Druggability (FPocket) 0.286
Structure A0A0H3H1U7
Pocket Pocket 7
ColabFold model
P2Rank 0.684 · Pocket 1
FPocket 0.542 · Pocket 36
Core conservation Conserved core gene
Roary core
CoreCruncher core
Gut microbiome 129 / 4744 genomes with a hit
Prevalence 2.7%

Metabolic context

Reactions catalyzed, pathway membership, and centrality in the genome-scale metabolic network.

Explore metabolic network

Metabolic context: more central than 96.1% of genes in this genome, no human homolog detected.

Relative network centrality 96.1% more central than 96.1% of genes in this genome
Chokepoint Not a chokepoint
Pathways
Pyruvate metabolism Valine, leucine and isoleucine biosynthesis
Catalyzed reaction

1 reaction mapped to this gene in the metabolic model. Open the full network to see each one, with substrates/products and the reaction-reaction map.

Imported from KpATCC43816.sbml · 2026-07-09

Sequence

Primary amino-acid sequence viewer.

MLSHPAEKYRPYPPIALPDRRWPDRQISHAPRWLSTDLRDGNQALAEPMDSARKLQFWDLLLECGFKEIEVAFPSASQTDFNFVRQLIDEQRIPEDVTIQVLTQARDPLILRTFEALRGARRATVHLYNATAPLFRELVFGMDKAEVIALATRATRLIRQQCEQQPETRWQYEYSPETFCFTEPEFALEICEAVADVWQPCAERPMIVNLPATVEVNTPNVYADQIEYFCRHFSRRGEVCISVHPHNDRGTGVASAELAVMAGADRVEGCLFGNGERTGNVCLVTLAMNLYSQGIDPELRFEQMNRVVEVVENCNQIPVHPRHPWAGSLAYTAFSGSHQDAIKKGFDARQPGDPWQMPYLPIDPQDIGCSYEAVIRVNSQSGKSGSAWLIEQNHGLKLPRGLQQDFSQHVQQATDSDGKEMTHHALWQLFRTRYGLQAQPALTLLDYQSASQQDGQLSLQATLRHHGETRRLQGQGNGLLSAAASGLSALFRQPFMIKDYHEHTLGARSDSRSVAYIRCVFPQGESYWGVGIDNDVARASLQALCNALSAADQAGGRK

Functional annotations

Enzyme classification and Gene Ontology terms linked to this protein.

1 EC 8 GO

Subcellular localization

Localization
Cytoplasmic

Enzyme Commission (EC)

1

Gene Ontology (GO)

8
  • GO:0003824 Catalysis of a biochemical reaction at physiological temperatures. In biologically catalyzed reactions, the reactants are known as substrates, and the catalysts are naturally occurring macromolecular substances known as enzymes. Enzymes possess specific binding sites for substrates, and are usually composed wholly or largely of protein, but RNA that has catalytic activity (ribozyme) is often also regarded as enzymatic.
  • GO:0003852 Catalysis of the reaction: 3-methyl-2-oxobutanoate + acetyl-CoA + H2O = (2S)-2-isopropylmalate + CoA + H+.
  • GO:0009098 The chemical reactions and pathways resulting in the formation of L-leucine, 2-amino-4-methylpentanoic acid.
  • GO:0019752 The chemical reactions and pathways involving carboxylic acids, any organic acid containing one or more carboxyl (COOH) groups or anions (COO-).
  • GO:0046912 Catalysis of the transfer of an acyl group from one compound (donor) to another (acceptor), with the acyl group being converted into alkyl on transfer.
  • GO:0005737 The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
  • GO:0003985 Catalysis of the reaction: 2 acetyl-CoA = CoA + acetoacetyl-CoA.
  • GO:0000287 Binding to a magnesium (Mg) ion.

Sequence domains and features

Domain and signature matches imported from InterPro and related databases.

27 records
Show feature table
Start End DB Term Name
10 374 Gene3D G3DSA:3.20.20.70 Aldolase class I
10 374 InterPro IPR013785 Aldolase-type TIM barrel
31 305 ProSiteProfiles PS50991 Pyruvate carboxyltransferase domain.
31 305 InterPro IPR000891 Pyruvate carboxyltransferase
1 552 PANTHER PTHR46911 -
38 54 ProSitePatterns PS00815 Alpha-isopropylmalate and homocitrate synthases signature 1.
38 54 InterPro IPR002034 Alpha-isopropylmalate/homocitrate synthase, conserved site
6 553 Hamap MF_00572 2-isopropylmalate synthase [leuA].
6 553 InterPro IPR005668 2-isopropylmalate synthase
5 551 NCBIfam TIGR00970 2-isopropylmalate synthase
5 551 InterPro IPR005668 2-isopropylmalate synthase
420 552 SMART SM00917 LeuA_dimer_2
420 552 InterPro IPR013709 2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain
241 254 ProSitePatterns PS00816 Alpha-isopropylmalate and homocitrate synthases signature 2.
241 254 InterPro IPR002034 Alpha-isopropylmalate/homocitrate synthase, conserved site
420 549 Pfam PF08502 LeuA allosteric (dimerisation) domain
420 549 InterPro IPR013709 2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain
20 328 SUPERFAMILY SSF51569 Aldolase
30 312 CDD cd07942 DRE_TIM_LeuA
30 312 InterPro IPR039371 LeuA, N-terminal catalytic TIM barrel domain
31 311 Pfam PF00682 HMGL-like
31 311 InterPro IPR000891 Pyruvate carboxyltransferase
375 551 Gene3D G3DSA:3.30.160.270 -
375 551 InterPro IPR036230 2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain superfamily
443 549 SUPERFAMILY SSF110921 2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain
443 549 InterPro IPR036230 2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain superfamily
387 434 SUPERFAMILY SSF89000 post-HMGL domain-like

3D structure

Selected loaded structure. Experimental PDB entries may cover only a portion of the sequence; AlphaFold DB and ColabFold models typically cover the full protein but remain computational predictions.

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Pocket score High Medium Low
How colors and pocket overlays are used
Uniform protein color marks the displayed model as a single molecular object.
Experimental PDB structures may be colored by chain to distinguish subunits or copies present in the file.
Pocket colors and alpha spheres are evidence overlays for predicted binding cavities; they are not alternative protein chains.
'Alpha spheres' is FPocket's own cavity-shape geometry, imported when available and aligned with the loaded structure.
'Pocket atoms'/'Predicted site atoms' show the pocket's residue atoms instead: P2Rank reports residues rather than alpha spheres, and FPocket falls back to this when alpha-sphere geometry is unavailable or doesn't align.
'No pocket geometry' means neither alpha spheres nor residue-position data could be found for that pocket; the layer just highlights the same residues as 'Nearby residues'.
Pocket details Inspect a specific pocket, or open the full viewer

Binding pockets · P2Rank

Druggability (P2Rank): high ≥ 0.5 · medium 0.2–0.49 · low < 0.2

Pocket 1 P2Rank #1
0.708
Likely same site as FPocket 2 0.5 Å 14 shared residues 93% of smaller site
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Surrounding area
Pocket 2 P2Rank #2
0.485
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Surrounding area
Pocket 3 P2Rank #3
0.05
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Surrounding area
Pocket 4 P2Rank #4
0.028
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Surrounding area
Pocket 5 P2Rank #5
0.011
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Surrounding area

Binding pockets · FPocket

Druggability (FPocket): high ≥ 0.7 · medium 0.4–0.69 · low < 0.4

Pocket 1 FPocket #7
0.286
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Surrounding area
Pocket 2 FPocket #2
0.251
Likely same site as P2Rank 1 0.5 Å 14 shared residues 93% of smaller site
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Surrounding area
Residue sets
UniProt: Binding site:244-244
UniProt: Binding site:246-246
UniProt: Binding site:280-280
UniProt: Binding site:40-40
All structural evidence 0 experimental · 2 predicted

Structural evidence

0 + 2

Experimental PDB entries plus predicted AlphaFold DB or ColabFold models. Click Switch to display a different loaded structure in the viewer.

Entry Method Resolution Chain Coverage Links Status
AlphaFold DB AF_A0A0H3H1U7
AlphaFold DB — — full sequence — Viewing
ColabFold VK055_4499
ColabFold — — full sequence — Loaded

Ligand evidence

Ligands grouped by evidence source. PDB ligands keep the source crystal visible, and loaded crystals can be opened directly in the structure viewer.

28 records
Chemistry signal

Structural ligand evidence is available for this target.

Direct evidence 0 same-protein records
Transferred evidence 8 records from similar proteins
Structural ligands 8 0 loaded crystals
Measured bioactivity 0 direct and transferred ChEMBL records
Proposed compounds 20 similarity-based ZINC candidates
Best available ligand signal
AKG PDB via homolog 146.1 Da · LogP -0.50 · TPSA 91.7 Open detail RCSB PDB
BPV PDB via homolog Detail RCSB PDB
COI PDB via homolog Detail RCSB PDB
FLC PDB via homolog Detail RCSB PDB
HCA PDB via homolog Detail RCSB PDB

Structural evidence inferred from similar proteins. The source crystal indicates where the ligand was observed; the UniProt column identifies the homologous protein carrying that ligand.

Show only:
Ligand Source crystal UniProt (homolog) MW · LogP · TPSA Lipinski PAINS SMILES
AKG RCSB PDB
2ZTJ
O87198 146.1 Da LogP -0.50 TPSA 91.7 ✓ Ro5 ✓ Clean C(CC(=O)O)C(=O)C(=O)O
BPV RCSB PDB
3HPZ
P9WQB3 167.0 Da LogP 0.03 TPSA 54.4 ✓ Ro5 ✓ Clean C(C(=O)C(=O)O)Br
COI RCSB PDB
3HPS
P9WQB3 130.1 Da LogP 0.69 TPSA 54.4 ✓ Ro5 ✓ Clean CC(C)CC(=O)C(=O)O
FLC RCSB PDB
3HQ1
P9WQB3 189.1 Da LogP -5.25 TPSA 140.6 ✓ Ro5 ✓ Clean C(C(=O)[O-])C(CC(=O)[O-])(C(=O)[O-])O
HCA RCSB PDB
2ZTK
O87198 206.1 Da LogP -0.86 TPSA 132.1 ✓ Ro5 ✓ Clean C(C[C@@](CC(=O)O)(C(=O)O)O)C(=O)O
KIV RCSB PDB
4OV4
B0SN40 116.1 Da LogP 0.30 TPSA 54.4 ✓ Ro5 ✓ Clean CC(C)C(=O)C(=O)O
KMT RCSB PDB
6E1J
C5J4P1 148.2 Da LogP 0.39 TPSA 54.4 ✓ Ro5 ✓ Clean CSCCC(=O)C(=O)O
VPM RCSB PDB
4OV9
B0SN40 176.2 Da LogP -0.07 TPSA 94.8 ✓ Ro5 ✓ Clean CC(C)[C@@](CC(=O)O)(C(=O)O)O

PDB and ChEMBL records on this protein are shown in full. ChEMBL records from similar proteins are capped at the top 100 per protein (by pchembl) and ZINC at the top 50 (Tanimoto ≥ 0.5). ADME columns are descriptor-based screening flags, not experimental toxicity results.

Cross-references

External database identifiers for this protein, its structures, ligands, and metabolic reactions.

Sequence

UniProt A0A0H3H1U7

Pathways

KEGG R01213 BioCyc 2-ISOPROPYLMALATESYN-RXN