Structural basis for induced fit mechanisms in DNA recognition by the Pdx1 homeodomain.
Pancreatic and duodenal homeobox 1 (Pdx1) is a homeodomain transcription factor belonging to the ParaHox family. Pdx1 plays an essential role in pancreatic endocrine and exocrine cell development and maintenance of adult islet beta-cell function. Mutations in the human pdx1 gene are linked to an early onset form of non-insulin-dependent diabetes mellitus, MODY-4. We demonstrate that the homeodomain reproduces the binding specificity of the full-length protein. We report the 2.4 A resolution crystal structure of the homeodomain bound to a target DNA. The two Pdx1/DNA complexes in the asymmetric unit display conformational differences: in the DNA curvature, the orientation of the homeodomain in the major groove, and the order of the N-terminal arm. Comparing the two complexes indicates invariant protein-DNA contacts, and variant contacts that are unique to each binding orientation. An induced fit model is proposed that depends on the DNA conformation and provides a mechanism for nonlocal contributions to binding specificity.
Longo
Antonella
A
Department of Molecular and Structural Biochemistry, 128 Polk Hall, North Carolina State University, Raleigh, North Carolina 27695, USA.
Guanga
Gerald P
GP
Rose
Robert B
RB
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006224:Cricetinae; D003460:Crystallization; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D008647:Mesocricetus; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D016415:Sequence Alignment; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA