- Predicted Function
- Oxidoreductase — EC 1, p=1.00. Astra confirms the enzyme class of a protein UniProt labels only "putative malate dehydrogenase" (activity never experimentally shown).
- Standout Pocket
- Pocket in the N-terminal extension. A HIGH-confidence pocket (0.88) whose top site sits in the ~180-residue N-terminal domain unique to MDH1B — not the conserved catalytic core — flagging that extension as functionally important.
- Architecture
- Soluble, ordered (~9% disorder): a unique N-terminal domain (~3–126), an NAD-binding Rossmann region, and a C-terminal LDH/MDH catalytic domain.
- Why It Matters
- An orphan enzyme (IDG Tdark); confirming its class and locating its distinctive domain is step one to a function.
- Clean Signal
- No membrane or amyloid signal.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
MDH1B is an enzyme in name only — so far. UniProt annotates it as a putative malate dehydrogenase (LDH/MDH superfamily) by sequence similarity alone; its catalytic activity has never been experimentally demonstrated, and it sits at IDG Tdark with no experimental structure in the PDB. It is also structurally odd: at 518 residues it is ~180 residues longer than canonical cytosolic MDH1 (~334 aa), carrying a dedicated N-terminal domain of unknown function ahead of the usual Rossmann and catalytic domains.
That combination — a "putative" enzyme with an extra domain and no structure — is exactly where prediction earns its keep: everything below is computed from the canonical 518-residue sequence and derived structural predictions, with no experimental MDH1B structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| N-terminal domain (unique) | 3–126 | Domain unique to MDH1B, of unknown function; carries the top-ranked predicted pocket. |
| NAD-binding (Rossmann) | 127–286 | Conserved cofactor-binding region. |
| LDH/MDH catalytic domain | 287–465 | Conserved catalytic domain carrying the expected dehydrogenase machinery. |
The Predicted Pocket
The Standout Pocket
HIGH confidence (0.88); no known binder. Astra's top-ranked pocket falls not in the conserved catalytic core but in the N-terminal extension that makes MDH1B unusual — reframing the biology: the domain that distinguishes MDH1B is also its most pocket-like, suggesting it binds something of its own.
Site: N-terminal domain (unique to MDH1B), residues ~12–84
Post-Translational & Structural Features
Specific, Testable Residues
- Ordered (~9% disorder), no amyloid. A foldable, expressible enzyme — the whole chain is a viable target for structural work.
- Three-part architecture. A unique N-terminal domain, an NAD-binding Rossmann region, and a C-terminal catalytic domain — clean boundaries for domain-by-domain expression.
- Testis-enriched expression. Consistent with a specialised, understudied metabolic enzyme.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| Oxidoreductase / MDH class | Malate / NAD(P) dehydrogenase activity assay | Confirm (or refute) catalysis + substrate |
| N-terminal-domain pocket (~12–84) | Express the N-terminal domain; ligand / fragment screen | A binding partner for the unique domain |
| Three-domain architecture | Domain-by-domain expression | Which domains fold independently |
| Catalytic core (Rossmann + MDH) | Cofactor binding + point mutants | Validates the predicted active machinery |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a substitute for a structure or an assay. No result here has been validated in the wet lab, and MDH1B's enzymatic activity has never been experimentally demonstrated.
- The pocket is predicted; no binder is named. The N-terminal-domain site is a residue-level hypothesis for the most ligand-like region, not a demonstrated ligandable pocket.
- No established disease link. Aggregator databases list MDH1B against several syndromes, but those are gene-name / family text-mining artefacts (the causative genes are different, e.g. MDH2 for DEE51); a single incidental somatic variant appears in a renal-carcinoma exome with no functional follow-up. We make no disease claim.
All predictions were generated with Orbion's Astra suite from the canonical MDH1B sequence (UniProt Q5I0G3), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q5I0G3 (MDH1B, human) — "Putative malate dehydrogenase 1B". uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. MDH1B target record — Tdark. pharos.nih.gov/targets/Q5I0G3.
- [3]Blum M., Chang H.-Y., et al. InterPro in 2022 (entry IPR063791, MDH1B N-terminal domain; MDH type-2 family). Nucleic Acids Res. 51(D1), D444–D456 (2023). https://doi.org/10.1093/nar/gkac993
- [4]Varela I., Tarpey P., Raine K., et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma (source of the incidental MDH1B L48I somatic variant). Nature 469, 539–542 (2011). https://doi.org/10.1038/nature09639
- [5]Bozkurt Ç., Vasilyeva A., Goteti A. AstraROLE2 & AstraSUIT2: Multi-Task Annotation Models for Functional Profiling of Proteins. bioRxiv 2025.06.21.660734 (2025). https://doi.org/10.1101/2025.06.21.660734
- [6]Bozkurt Ç., Vasilyeva A., Goteti A. AstraPTM2: A Context-Aware Transformer for Broad-Spectrum PTM Prediction. bioRxiv 2025.10.03.680341 (2025). https://doi.org/10.1101/2025.10.03.680341
- [7]Goteti A., Vasilyeva A., Bozkurt Ç. AstraBIND: Graph Attention Network for Predicting Ligand Binding Sites. bioRxiv 2025.11.10.687555 (2025). https://doi.org/10.1101/2025.11.10.687555