tooluniverse-structural-proteomics

Compare original and translation side by side

🇺🇸

Original

English

🇨🇳

Translation

Chinese

Structural Proteomics for Drug Target Validation

用于药物靶点验证的结构蛋白质组学

Comprehensive structural data integration using ToolUniverse tools across PDB, AlphaFold, GPCRdb, SAbDab, and proteomics databases for drug target validation.

通过ToolUniverse工具整合PDB、AlphaFold、GPCRdb、SAbDab及蛋白质组学数据库的全面结构数据，以实现药物靶点验证。

LOOK UP DON'T GUESS

有据可依，勿凭空猜测

PDB structures/resolutions:

PDBeSIFTS_get_best_structures

and

RCSBGraphQL_get_structure_summary

AlphaFold confidence:
```
alphafold_get_summary
```

Ligands/affinities:

PDBe_get_structure_ligands

and

BindingDB_get_ligands_by_uniprot

Druggability:
```
ProteinsPlus_predict_binding_sites
```

PDB结构/分辨率：

PDBeSIFTS_get_best_structures

和

RCSBGraphQL_get_structure_summary

AlphaFold置信度：
```
alphafold_get_summary
```

配体/亲和力：

PDBe_get_structure_ligands

和

BindingDB_get_ligands_by_uniprot

成药性：
```
ProteinsPlus_predict_binding_sites
```

COMPUTE, DON'T DESCRIBE

执行计算，勿仅描述

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

当分析需要计算（统计、数据处理、评分、富集分析）时，通过Bash编写并运行Python代码。不要描述你会怎么做——直接执行并报告实际结果。使用ToolUniverse工具获取数据，再通过Python（pandas、scipy、statsmodels、matplotlib）进行分析。

Domain Reasoning

领域推理

Resolution determines valid conclusions: <2A = atom positions visible; 2-3A = side chains reliable, drug design supported; >3A = backbone only, binding site unreliable. Do not over-interpret low-resolution structures.

分辨率决定结论的有效性：<2Å = 可观测原子位置；2-3Å = 侧链可靠，支持药物设计；>3Å = 仅可见主链，结合位点不可靠。请勿过度解读低分辨率结构。

Tool Inventory

工具清单

PDB (RCSB)

RCSBAdvSearch_search_structures

(query_type, query_value, rows),

RCSBData_get_entry

(entry_id),

RCSBGraphQL_get_structure_summary

(pdb_id),

RCSBGraphQL_get_ligand_info

(pdb_id),

RCSB_get_chemical_component

(comp_id)

RCSBAdvSearch_search_structures

(query_type, query_value, rows),

RCSBData_get_entry

(entry_id),

RCSBGraphQL_get_structure_summary

(pdb_id),

RCSBGraphQL_get_ligand_info

(pdb_id),

RCSB_get_chemical_component

(comp_id)

PDB (PDBe)

pdbe_get_entry_summary

(pdb_id),

PDBe_get_structure_ligands

(pdb_id),

PDBe_get_bound_molecules

(pdb_id),

PDBeSearch_search_structures

(query, rows),

PDBeSIFTS_get_best_structures

(uniprot_id),

PDBeSIFTS_get_all_structures

(uniprot_id),

PDBe_KB_get_ligand_sites

(pdb_id),

PDBe_KB_get_interface_residues

(pdb_id),

PDBeValidation_get_quality_scores

(pdb_id)

pdbe_get_entry_summary

(pdb_id),

PDBe_get_structure_ligands

(pdb_id),

PDBe_get_bound_molecules

(pdb_id),

PDBeSearch_search_structures

(query, rows),

PDBeSIFTS_get_best_structures

(uniprot_id),

PDBeSIFTS_get_all_structures

(uniprot_id),

PDBe_KB_get_ligand_sites

(pdb_id),

PDBe_KB_get_interface_residues

(pdb_id),

PDBeValidation_get_quality_scores

(pdb_id)

PDBe PISA

PDBePISA_get_interfaces

(pdb_id),

PDBePISA_get_assemblies

(pdb_id)

PDBePISA_get_interfaces

(pdb_id),

PDBePISA_get_assemblies

(pdb_id)

AlphaFold

alphafold_get_prediction

(qualifier=UniProt),

alphafold_get_summary

(qualifier),

alphafold_get_annotations

(qualifier)

alphafold_get_prediction

(qualifier=UniProt),

alphafold_get_summary

(qualifier),

alphafold_get_annotations

(qualifier)

Binding Sites

结合位点

ProteinsPlus_predict_binding_sites

(pdb_id, chain),

BindingDB_get_ligands_by_uniprot

(uniprot_id),

BindingDB_get_ligands_by_pdb

(pdb_id),

BindingDB_get_targets_by_compound

(smiles)

ProteinsPlus_predict_binding_sites

(pdb_id, chain),

BindingDB_get_ligands_by_uniprot

(uniprot_id),

BindingDB_get_ligands_by_pdb

(pdb_id),

BindingDB_get_targets_by_compound

(smiles)

Foldseek

Foldseek_search_structure

(sequence, mode="tmalign"),

Foldseek_get_result

(ticket)

Foldseek_search_structure

(sequence, mode="tmalign"),

Foldseek_get_result

(ticket)

GPCRdb

GPCRdb_get_protein

(protein),

GPCRdb_get_structures

(protein),

GPCRdb_get_ligands

(protein),

GPCRdb_get_mutations

(protein). Accepts entry names, gene symbols (auto-converted to

{symbol.lower()}_human

), or UniProt accessions.

GPCRdb_get_protein

(protein),

GPCRdb_get_structures

(protein),

GPCRdb_get_ligands

(protein),

GPCRdb_get_mutations

(protein)。接受条目名称、基因符号（自动转换为

{symbol.lower()}_human

）或UniProt accession号。

SAbDab

SAbDab_search_structures

(query/antigen),

SAbDab_get_structure

(pdb_id),

TheraSAbDab_search_therapeutics

(query),

TheraSAbDab_search_by_target

(target)

SAbDab_search_structures

(query/antigen),

SAbDab_get_structure

(pdb_id),

TheraSAbDab_search_therapeutics

(query),

TheraSAbDab_search_by_target

(target)

Domains

结构域

InterPro_get_protein_domains

(uniprot_id),

Pfam_get_protein_annotations

(uniprot_id),

UniProt_get_entry_by_accession

(accession)

InterPro_get_protein_domains

(uniprot_id),

Pfam_get_protein_annotations

(uniprot_id),

UniProt_get_entry_by_accession

(accession)

Proteomics

蛋白质组学

ProteomeXchange_search_datasets

(query),

ProteomeXchange_get_dataset

(dataset_id)

ProteomeXchange_search_datasets

(query),

ProteomeXchange_get_dataset

(dataset_id)

Workflow 1: Find All Structures for a Drug Target

工作流1：查找药物靶点的所有结构

Phase 0: Resolve protein → UniProt ID, gene symbol, organism
Phase 1: PDBeSIFTS_get_best_structures → RCSBGraphQL_get_structure_summary → PDBeValidation
Phase 2: alphafold_get_prediction/summary → compare pLDDT with experimental coverage
Phase 3: IF GPCR → GPCRdb; IF antibody target → SAbDab/TheraSAbDab
Phase 4: InterPro/Pfam domain mapping → identify unresolved regions
Phase 5: Summary table (PDB ID, method, resolution, ligands, coverage, quality)

Decisions: Resolution <2.5A for drug design. X-ray > Cryo-EM > NMR > AlphaFold for binding sites. Holo > apo structures.

Phase 0: 解析蛋白质 → UniProt ID、基因符号、物种
Phase 1: PDBeSIFTS_get_best_structures → RCSBGraphQL_get_structure_summary → PDBeValidation
Phase 2: alphafold_get_prediction/summary → 对比pLDDT与实验覆盖范围
Phase 3: 若为GPCR → GPCRdb；若为抗体靶点 → SAbDab/TheraSAbDab
Phase 4: InterPro/Pfam结构域映射 → 识别未解析区域
Phase 5: 汇总表格（PDB ID、方法、分辨率、配体、覆盖范围、质量）

决策依据：药物设计需分辨率<2.5Å。结合位点优先级：X射线 > 冷冻电镜 > NMR > AlphaFold。结合态结构 > apo结构。

Workflow 2: Identify Binding Pocket Ligands

工作流2：识别结合口袋配体

Phase 1: PDBe_get_structure_ligands + RCSBGraphQL_get_ligand_info + PDBe_KB_get_ligand_sites
Phase 2: ProteinsPlus_predict_binding_sites → druggability score, pocket residues
Phase 3: BindingDB_get_ligands_by_pdb/uniprot → Ki, Kd, IC50
Phase 4: RCSB_get_chemical_component for key ligands

Filter artifacts: GOL, EDO, SO4, PEG, ACT, CL, NA. Keep cofactors (ATP, NAD, HEM) and catalytic metals (ZN, MG) if relevant.

Phase 1: PDBe_get_structure_ligands + RCSBGraphQL_get_ligand_info + PDBe_KB_get_ligand_sites
Phase 2: ProteinsPlus_predict_binding_sites → 成药性评分、口袋残基
Phase 3: BindingDB_get_ligands_by_pdb/uniprot → Ki、Kd、IC50
Phase 4: RCSB_get_chemical_component 获取关键配体信息

过滤人工产物：过滤GOL、EDO、SO4、PEG、ACT、CL、NA。若相关则保留辅因子（ATP、NAD、HEM）和催化金属（ZN、MG）。

Workflow 3: Cross-Validate Drug Binding

工作流3：交叉验证药物结合

Phase 1: Find co-crystal structures → filter for drug/analogs
Phase 2: BindingDB affinity data (Ki, Kd, IC50)
Phase 3: ProteinsPlus + PDBe-KB binding site characterization
Phase 4: PDBeValidation quality → binding site well-resolved?
Phase 5: AlphaFold + Foldseek structural comparison
Phase 6: GPCR-specific (if applicable) → active/inactive states, pharmacology, resistance mutations
Phase 7: Antibody-specific (if applicable) → epitope mapping
Phase 8: Evidence integration

Phase 1: 查找共晶结构 → 筛选药物/类似物
Phase 2: BindingDB亲和力数据（Ki、Kd、IC50）
Phase 3: ProteinsPlus + PDBe-KB结合位点特征分析
Phase 4: PDBeValidation质量评估 → 结合位点是否解析良好？
Phase 5: AlphaFold + Foldseek结构对比
Phase 6: 若为GPCR特异性 → 活性/非活性状态、药理学、耐药突变
Phase 7: 若为抗体特异性 → 表位定位
Phase 8: 整合证据

Tool Parameter Gotchas

工具参数注意事项

Tool	Mistake	Correct
`alphafold_get_prediction/summary`	`uniprot_id`	`qualifier`
`GPCRdb_get_protein`	`gene_name`	`protein`
`PDBeSIFTS_get_best_structures`	gene symbol	`uniprot_id` (e.g., "P04637")
`Foldseek_search_structure`	`mode="3diaa"`	`mode="tmalign"`
`SAbDab_search_structures`	`name`	`query` or `antigen`
`RCSB_get_chemical_component`	`ligand_id`	`comp_id`

工具	常见错误	正确用法
`alphafold_get_prediction/summary`	使用 `uniprot_id`	使用 `qualifier`
`GPCRdb_get_protein`	使用 `gene_name`	使用 `protein`
`PDBeSIFTS_get_best_structures`	使用基因符号	使用 `uniprot_id` （例如："P04637"）
`Foldseek_search_structure`	使用 `mode="3diaa"`	使用 `mode="tmalign"`
`SAbDab_search_structures`	使用 `name`	使用 `query` 或 `antigen`
`RCSB_get_chemical_component`	使用 `ligand_id`	使用 `comp_id`

Evidence Grading

证据分级

Tier	Confidence
T1	Co-crystal (<2.5A) + binding affinity data
T2	Experimental structure + computational prediction
T3	AlphaFold + pocket analysis + known ligand analogs
T4	Homology model or low-resolution only

等级	置信度
T1	共晶结构（<2.5Å）+ 结合亲和力数据
T2	实验结构 + 计算预测
T3	AlphaFold + 口袋分析 + 已知配体类似物
T4	仅同源模型或低分辨率结构

Interpretation

解读标准

Metric	High	Acceptable	Caution
Resolution	<2.0A (X-ray) / <3.0A (cryo-EM)	2.0-2.5A / 3.0-4.0A	>3.0A / >4.5A
R-free	<0.25	0.25-0.30	>0.30
AlphaFold pLDDT	>90	70-90	<70 (disordered)

DoGSiteScorer >0.6 = druggable; <0.4 = unlikely druggable. PISA assemblies should be cross-validated with SEC-MALS/native MS.

指标	优秀	可接受	需谨慎
分辨率	<2.0Å（X射线）/ <3.0Å（冷冻电镜）	2.0-2.5Å / 3.0-4.0Å	>3.0Å / >4.5Å
R-free	<0.25	0.25-0.30	>0.30
AlphaFold pLDDT	>90	70-90	<70（无序区域）

DoGSiteScorer得分>0.6 = 具有成药性；<0.4 = 成药性低。PISA组装体需通过SEC-MALS/天然质谱交叉验证。

Limitations

局限性

BindingDB: 60s+ for popular targets
AlphaFold: lacks ligand context
GPCRdb: Class A-F GPCRs only
PDBePISA:
```
operation
```
is internal, not a public parameter

BindingDB：热门靶点查询需60秒以上
AlphaFold：缺乏配体相关上下文
GPCRdb：仅支持A-F类GPCR
PDBePISA：
```
operation
```
为内部参数，非公开参数