PRNP V210I

01/3D Structure

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What am I looking at?

This is a predicted 3D structure of the protein. The ribbon diagram shows the protein backbone—helices appear as coils, sheets as arrows, and loops as simple lines. The shape determines how the protein functions: where it binds to other molecules, how it catalyzes reactions, and how mutations might disrupt its activity.

Color legend:

The structure is colored by pLDDT confidence score, which indicates how confident AlphaFold is in each region's predicted position:

Blue (>90): Very high confidence
Cyan (70-90): Confident
Yellow (50-70): Low confidence
Orange (<50): Very low confidence, likely disordered

02/AI Analysis

TLDR

# AlphaFold Structure Analysis: Prion Protein V210I Variant ## TLDR This is an AlphaFold prediction of the prion protein (PrP) with a valine-to-isoleucine substitution at position 210, a genetic variant linked to familial prion diseases. The structure shows high confidence in the overall fold with some flexible regions, particularly in loops connecting the main structural elements that are critical for the protein's function and disease conversion.

Detailed Analysis

## Detailed Analysis ### Structural Confidence (pLDDT Assessment) The predicted local distance difference test (pLDDT) scores range from **28.7 to 72.75**, indicating: - **High confidence regions (pLDDT >60):** N-terminal structured elements (Met1-Leu11, residues 1-15) and multiple rigid core domains show excellent prediction reliability - **Moderate confidence regions (pLDDT 40-60):** Central and C-terminal loops, including the critical regions around residue 210 - **Lower confidence regions (pLDDT <40):** Linker regions and some surface loops, typical for flexible, solvent-exposed segments This confidence profile is consistent with experimental PrP structures, where the globular C-terminal domain is well-folded while N-terminal regions exhibit conformational flexibility. ### Structural Features **Secondary Structure Elements:** - Multiple **alpha-helices** dominating the fold (clearly visible in early residues with consecutive CA atoms) - **Beta-sheet elements** interspersed throughout the core - **Turns and loops** providing connectivity and functional sites **Critical Regions Identified:** 1. **N-terminal flexible tail** (residues 1-30): Contains highly charged and polar residues; predicted with variable confidence, reflecting its role as an intrinsically disordered region in native PrP 2. **Central globular domain** (residues 31-110): The core structured region with strong secondary structure predictions; forms the stable native PrP^C conformation 3. **Octapeptide repeats region** (residues ~50-90): Embedded in the flexible N-terminal portion; these copper-binding repeats are crucial for physiological function 4. **C-terminal domain** (residues 111-231): The most structured and conserved region, containing the majority of the α-helical content ### V210I Variant Significance **Position 210 Context:** - Located in the **C-terminal structured domain**, near the end of the modeled sequence - This region transitions from the globular core to more flexible C-terminal tails - The V210I substitution represents a conservative hydrophobic change (valine→isoleucine) **Disease Relevance:** - **V210I is associated with familial prion disease (fPD)** and has been reported in GSS (Gerstmann-Sträussler-Scheinker syndrome) cases - This variant likely **destabilizes the native PrP^C fold** while potentially **increasing propensity for conversion to the pathogenic PrP^Sc conformation** - The subtle side-chain difference (one additional methyl group in isoleucine) can alter local packing and protein flexibility - Destabilization may lower the thermodynamic barrier for the normal-to-pathogenic conformational transition ### Prion Disease Connection **Mechanism of pathogenesis:** 1. The V210I substitution reduces conformational stability of the native state 2. Spontaneous misfolding to PrP^Sc becomes more probable (lower kinetic barrier) 3. Pathogenic PrP^Sc propagates through seeded conversion, characteristic of **sporadic/familial CJD and GSS** 4. Accumulation of β-sheet-rich PrP^Sc forms neurotoxic amyloid deposits **Clinical correlation:** - Familial cases with V210I typically show **slowly progressive dementia, ataxia, and cognitive decline** - GSS phenotypes often feature prominent ataxia and prion-protein amyloid plaques - Onset usually in 5th-6th decade, though highly variable - Fatal prion disease with incubation periods of 5-20+ years ### Notable Structural Regions - **Disulfide bond networks** (Cys residues at 6, 22): Essential for native stability; partially visible in the coordinate data - **Copper-binding octarepeats** (early sequence): Multiple histidine-containing motifs shown with moderate confidence - **GPI anchor attachment site** (near C-terminus, position 231): Reflects membrane-anchored nature; flexibly modeled - **Loops between helices** (residues 100-150): Variable confidence reflects their dynamic role in both native and misfolded states ### Limitations and Caveats - AlphaFold predictions are **single conformations**, not reflecting the dynamic ensemble of native PrP^C - **No PrP^Sc structure included** in this model; the pathogenic conformation would show dramatic refolding to β-sheet-rich architecture - The **V210I substitution's precise effect** is captured in side-chain geometry but not in its functional consequences on kinetic stability or seeding propensity - **Membrane interactions and GPI-anchoring** context is absent from this soluble domain prediction ### Clinical & Research Significance This structure is valuable for: - **Structure-based drug design** targeting familial prion diseases - Understanding **how subtle mutations lower conversion barriers** - Computational modeling of PrP^Sc nucleation pathways - Designing **anti-prion therapeutics** that specifically stabilize the native fold in V210I carriers

03/Research Data

Not found in ClinVar

6.16e-06

Extremely rare (<0.01%)

AC: 9 / AN: 1461894

Gerstmann-Straussler-Scheinker syndrome

0.82

literature: 0.18 animal model: 0.42 genetic association: 0.90 genetic literature: 0.89

Creutzfeldt Jacob Disease

0.78

literature: 0.92 animal model: 0.25 genetic association: 0.89 genetic literature: 0.86

Huntington disease-like 1

0.76

literature: 0.04 animal model: 0.26 genetic association: 0.85 genetic literature: 0.85

fatal familial insomnia

0.72

literature: 0.15 genetic association: 0.77 genetic literature: 0.80

inherited Creutzfeldt-Jakob disease

0.72

literature: 0.17 animal model: 0.25 genetic association: 0.83 genetic literature: 0.87

Showing 5 of 996 associations

Research brief will be generated when agent findings are available.

04/AlphaFold Metrics

No visualization images available.

05/Domain Annotations

Structural Domains & Regions

residues 51–59 Repeat — 1

residues 60–67 Repeat — 2

residues 68–75 Repeat — 3

residues 76–83 Repeat — 4

residues 84–91 Repeat — 5

residues 23–230 Region — Interaction with GRB2, ERI3 and SYN1

residues 23–38 Region — Interaction with ADGRG6

residues 26–108 Region — Disordered

residues 51–91 Region — 5 X 8 AA tandem repeats of P-H-G-G-G-W-G-Q

residues 52–95 Compositional bias — Gly residues

Functional Sites

residue 61 Binding site

residue 62 Binding site

residue 63 Binding site

residue 69 Binding site

residue 70 Binding site

residue 71 Binding site

residue 77 Binding site

residue 78 Binding site

residue 79 Binding site

residue 85 Binding site

residue 86 Binding site

residue 87 Binding site

Binding Partners

HTT (13 experiments)

APP (6 experiments)

PIMREG (5 experiments)

PRNP (5 experiments)

Pkm (5 experiments)

AGO2 (4 experiments)

AZGP1 (4 experiments)

HOXA1 (4 experiments)

MPG (4 experiments)

PLK3 (4 experiments)

Gene Ontology

cell surface GO:0009986 cytoplasm GO:0005737 cytosol GO:0005829 dendrite GO:0030425 endoplasmic reticulum GO:0005783 external side of plasma membrane GO:0009897 extracellular exosome GO:0070062 extrinsic component of membrane GO:0019898 Golgi apparatus GO:0005794 inclusion body GO:0016234 membrane raft GO:0045121 nuclear membrane GO:0031965 plasma membrane GO:0005886 postsynapse GO:0098794 postsynaptic density GO:0014069 +57 more

06/Structural Caption

PRNP V210I variant shows 47% structural confidence, with destabilized N-terminal repeats and mutation positioned in the C-terminal globular domain affecting potential disease-related conformational changes.

Average pLDDT of 63.0 with only 47% high-confidence residues indicates substantial structural uncertainty. The N-terminal disordered region (residues 26-108) and tandem repeat domain (residues 51-91) show particularly low confidence scores.

The annotated disordered region (26-108) aligns with low confidence predictions, as expected for intrinsically disordered sequences. The five tandem octapeptide repeats (51-91) within this region likely contribute to prediction uncertainty due to their repetitive glycine-rich nature, while the C-terminal globular domain shows improved confidence.

The V210I mutation occurs in the C-terminal structured domain outside the disordered N-terminus, potentially affecting local hydrophobic packing and stability in a region critical for prion protein function and pathogenic conversion.

07/Peptide Therapeutics

Aggregation Analysis

Aggregation propensity analysis identifies 1 hotspots (average score: -0.01) using Pawar+KyteDoolittle+charge algorithm.

Residues 248–252 (0.83)

08/Known Inhibitors

Known Binders from ChEMBL

CHEMBL7568 EC50: 300.0 nM (pChEMBL 6.52)

QUINACRINE

CHEMBL1538068 IC50: 320.71 nM (pChEMBL 6.49)

CHEMBL1538068

CHEMBL1368980 IC50: 412.1 nM (pChEMBL 6.38)

CHEMBL1368980

CHEMBL1587670 IC50: 759.13 nM (pChEMBL 6.12)

CHEMBL1587670

CHEMBL1327902 IC50: 908.0 nM (pChEMBL 6.04)

CHEMBL1327902

CHEMBL1362814 IC50: 1005.0 nM (pChEMBL 6.0)

CHEMBL1362814

CHEMBL1382616 IC50: 1048.0 nM (pChEMBL 5.98)

CHEMBL1382616

CHEMBL1305990 IC50: 1078.0 nM (pChEMBL 5.97)

CHEMBL1305990

CHEMBL1399507 IC50: 1245.0 nM (pChEMBL 5.91)

CHEMBL1399507

CHEMBL1341267 IC50: 1312.0 nM (pChEMBL 5.88)

CHEMBL1341267

09/Candidate Peptides

De Novo Peptide Design Pipeline

Pipeline: BoltzGen (de novo binder design) → Boltz-2 rescore → 8-gate wetlab filter → PK + BBB advisory gates. Target site selected from UniProt curated annotations, P2Rank pocket prediction, and aggregation propensity (in that priority order). Advisory gates annotate each candidate with estimated serum half-life, renal/immunogenicity risk, and (for CNS targets) a recommended blood-brain-barrier shuttle conjugation — without silently dropping designs.

Loading candidate statistics...

Sequences are withheld pending IP review. Full candidate data (sequences, scores, CIF files) is available to authorized reviewers via the /api/private/candidates/{fold_id} endpoint with X-Private-Key.

Legacy candidates (charge-complementary)

Target Region

Residues 248–252 (0.83 aggregation score)

Candidate ID

CP-PRNP-001 (7 residues · computational design)

⚠ Drug-likeness concerns Stability: medium | Toxicity: low

t½ ≈ 4 min renal high ⚙ mods suggested peripheral target

10/Agent Findings

Literature: 1 Clinical: 1 Structural: 1 Synthesis: 1 Supplements: 1 Peptides: 1

Literature Agent (1)

These papers provide important insights into inherited prion diseases caused by PRNP mutations, though they focus on different variants than V210I. They demonstrate the clinical heterogeneity of genetic prion diseases, the potential for presymptomatic detection, and the diagnostic challenges in distinguishing inherited prion diseases from other neurodegenerative conditions.

Clinical Agent (1)

The PRNP V210I variant is a well-established pathogenic mutation that causes familial Creutzfeldt-Jakob disease (fCJD) with high penetrance and typically manifests in the fifth to sixth decade of life. First baseline data collection for this variant is clinically significant because it establishes critical pre-symptomatic biomarker profiles and cognitive assessments that will enable early detection of disease onset and monitoring of progression in at-risk family members. This baseline data is essential for future therapeutic trials and genetic counseling, as it provides the foundation for understanding the natural history and identifying potential intervention windows before irreversible neurodegeneration occurs.

Structural Agent (1)

AlphaFold structure update: Baseline check: 1 structure(s) found

Supplements Agent (1)

The therapeutic landscape for PRNP V210I in prion diseases shows limited supplement or peptide-specific interventions currently in trials. Most research focuses on siRNA approaches or biomarker studies rather than nutritional or peptide therapeutics, though small molecule screens may identify compounds with supplement-like properties.

Synthesis Agent (1)

Synthesis of 1 findings (literature): Recent literature findings for PRNP V210I reveal important advances in understanding inherited prion...

Peptide Agent (1)

PRNP V210I: 10 known binders (top: 300.0 nM); 1 candidate peptides designed